EP4 receptor antagonists

ABSTRACT

Compounds of formula (I):  
                 
 
     wherein: R 2  is H or an optionally substituted C 1-4  alkyl group; Y is either —(CH 2 ) n —X—, where n is 1 or 2 and X is O, S, S(═O), S(═O) 2 , or NR N1 , where R N1  is selected from H or optionally substituted C 1-4  alkyl, or Y is —C(═O)NR N2 —, where R N2  is selected from H, and optionally substituted C 1-7  alkyl or C 5-20  aryl; R 3  is an optionally substituted C 6  aryl group linked to a further optionally substituted C 6  aryl group, wherein if both C 6  aryl groups are benzene rings, there may be an oxygen bridge between the two rings, bound adjacent the link on both rings; A is a single bond or a C 1-3  alkylene group; and R 5  is either:  
     (i) carboxy;  
     (ii) a group of formula (II):  
                 
 
     or  
     (iii) a group of formula (III):  
                 
 
      wherein R is optionally substituted C 1-7  alkyl, C 5-20  aryl or NR N3 R N4 , where R N3  and R N4  are independently selected from optionally substituted C 1-4  alkyl;  
     (iv) tetrazol-5-yl.

[0001] This invention relates to EP₄ receptor antagonists,pharmaceutical compositions comprising such compounds, and the use ofsuch compounds and compositions to treat various diseases.

BACKGROUND TO THE INVENTION

[0002] Prostanoids comprise prostaglandins (PGs) and thromboxanes (Txs)and their receptors fall into five different classes (DP, EP, FP, IP andTP) based on their sensitivity to the five naturally occurringprostanoids, PGD₂, PGE₂, PGF_(2α), PGI₂ and TxA₂, respectively (Coleman,R. A., Prostanoid Receptors. IUPHAR compendium of receptorcharacterisation and classification, 2^(nd) edition, 338-353, ISBN0-9533510-3-3, 2000). EP receptors (for which the endogenous ligand isPGE₂) have been subdivided into four types termed EP₁, EP₂, EP₃ and EP₄.These four types of EP receptors have been cloned and are distinct atboth a molecular and pharmacological level (Coleman, R. A., 2000)

[0003] EP₄ antagonists have been shown to be useful in the treatment ofpain, and in particular, in the treatment of primary headache disorders,which include migraines, and secondary headache disorders, such asdrug-induced headaches (WO 00/18405 and WO 01/72302). Dilation of thecerebral vasculature and the subsequent stimulation of pain stimulating,perivascular trigeminal sensory afferent nerves is recognised to play animportant role in the pathophysiology of migraine. A sterileinflammatory response, associated with activation of cycloxygenase andthe generation of PGE₂, is also implicated in the pathophysiology ofmigraine. PGE₂ levels have been shown to be raised during migraineattacks and PGE₂ contributes to the pain of migraine by directlydilating cerebral arteries and by stimulating the release ofvasoactive/pro-inflammatory peptides from the trigeminal nerves. Theseeffects of PGE₂ are mediated in whole or in part by EP₄ receptors. Thus,by binding to and preventing the stimulation of EP₄ receptors, EP₄antagonists may be used to treat the pain of migraine.

[0004] EP₄ antagonists may also be useful in treating a number of otherconditions and diseases. For example, they may be used in:

[0005] the treatment of pain associated with rheumatoid arthritis,osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenilearthritis;

[0006] the treatment of musculoskeletal pain, lower back and neck pain,sprains and strains, neuropathic pain, sympathetically mediated pain,myositis, pain associated with cancer and fibromyalgia, pain associatedwith influenza or other viral infections, such as the common cold,rheumatic fever; pain associated with bowel disorders such as non-ulcerdyspepsia, irritable bowel syndrome; non-cardiac chest pain, painassociated with myocardial ischaemia, post-operative pain, headache,toothache and dysmenorrhea. Neuropathic pain syndromes include diabeticneuropathy, sciatica, non-specific lower back pain, multiple sclerosispain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia,trigeminal neuralgia and pain resulting from physical trauma;

[0007] the treatment of inflammatory diseases including rheumatoid andosteoarthritis, psoriasis, dermatitis, retinitis, conjunctivitis,asthma, bronchitis, chronic obstructive pulmonary disease, inflammatorybowel disease, colitis, nephritis, gingivitis and hepatitis;

[0008] the treatment of cancers including familial adenomatouspolyposis, endometrial carcinoma, colorectal and cervical cancer;

[0009] the treatment of bone disorders involving altered bone formationor resorption such as osteoporosis;

[0010] women's health for the treatment of myometrial and endometrialdisorders;

[0011] the treatment of gastrointestinal disease including diarrhoea;

[0012] the treatment of immunological disorders such as autoimmunedisease, immunological deficiency diseases, organ transplantation andincreasing the latency of HIV infection; the treatment of diseases ofabnormal platelet function. (e.g. occlusive vascular diseases);

[0013] the preparation of a drug with diuretic properties to treat orprevent various oedema, hypertension, premenstrual tension, urinarycalculus, oliguria, hyperphosphaturia, mesangial proliferativeglomerulonephritis, chronic renal failure or the like;

[0014] the treatment of impotence or erectile dysfunction, and femalesexual dysfunction;

[0015] the treatment of hair growth disorders;

[0016] the treatment of sleep disorders such as narcolepsy and insomnia;

[0017] the treatment of cardiovascular diseases and shock statesassociated with hypotension (e.g. septic shock);

[0018] the treatment of neurodegenerative diseases and for preventingneuronal damage following stroke, cardiac arrest, cardiopulmonarybypass, traumatic brain injury or spinal cord injury;

[0019] the treatment of tinnitus;

[0020] the treatment of dependence; and

[0021] the treatment of complications of diabetes.

[0022] Although EP₄ antagonists are known, it is desired to find novelEP₄ antagonists, and in particular, EP₄ antagonists which are selectiveagainst other EP receptors, i.e. EP₁, EP₂ and EP₃.

SUMMARY OF THE INVENTION

[0023] A first aspect of the present invention provides a compound offormula (I):

[0024] or a pharmaceutically acceptable salt thereof for use in a methodof therapy, wherein:

[0025] R² is H or an optionally substituted C₁₋₄ alkyl group;

[0026] Y is either —(CH₂)_(n)—X—, where n is 1 or 2 and X is O, S,S(═O), S(═O)₂, or NR^(N1), where R^(N1) is selected from H or optionallysubstituted C₁₋₄ alkyl, or Y is —C(═O)NR^(N2)—, where R^(N2) is selectedfrom H, and optionally substituted C₁₋₇ alkyl or C₅₋₂₀ aryl;

[0027] R³ is an optionally substituted C₆ aryl group linked to a furtheroptionally substituted C₆ aryl group, wherein if both C₆ aryl groups arebenzene rings, there may be an oxygen bridge between the two rings,bound adjacent the link on both rings;

[0028] A is a single bond or a C₁₋₃ alkylene group; and

[0029] R⁵ is either:

[0030] (i) carboxy;

[0031] (ii) a group of formula (II):

[0032]  or

[0033] (iii) a group of formula (III):

[0034]  wherein R is optionally substituted C₁₋₇ alkyl, C₅₋₂₀ aryl orNR^(N3)R^(N4), where R^(N3) and R^(N4) are independently selected fromoptionally substituted C₁₋₄ alkyl;

[0035] (iv) tetrazol-5-yl.

[0036] A second aspect of the present invention provides a compound offormula (I):

[0037] or a salt, solvate and chemically protected form thereof,wherein:

[0038] R² is H or an optionally substituted C₁₋₄ alkyl group;

[0039] Y is either —(CH₂)_(n)—X—, where n is 1 or 2 and X is O, S,S(═O), S(═O)₂ or NR^(N1), where R^(N1) is selected from H or optionallysubstituted C₁₋₄ alkyl, or Y is —C(═O)NR^(N2)—, where R^(N2) is selectedfrom H, and optionally substituted C₁₋₇ alkyl or C₅₋₂₀ aryl;

[0040] R³ is an optionally substituted C₆ aryl group linked to a furtheroptionally substituted C₆ aryl group, wherein if both C₆ aryl groups arebenzene rings, there may be an oxygen bridge between the two rings,bound adjacent the link on both rings;

[0041] A is a single bond or a C₁₋₃ alkylene group; and

[0042] R⁵ is either:

[0043] (i) carboxy;

[0044] (ii) a group of formula (II):

[0045]  or

[0046] (iii) a group of formula (III):

[0047]  wherein R is optionally substituted C₁₋₇ alkyl, C₅₋₂₀ aryl orNR^(N3)R^(N4), where R^(N3) and R^(N4) are independently selected fromoptionally substituted C₁₋₄ alkyl;

[0048] (iv) tetrazol-5-yl,

[0049] except that when R² is methyl, Y is —CH₂—O— and R⁵ is carboxy orC₁₋₇ alkyl ester thereof, then R³ is not:

[0050] A third aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) as defined in the firstaspect or a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.

[0051] A further aspect of the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof inthe preparation of a medicament for the treatment of a conditionalleviated by antagonism of an EP₄ receptor.

[0052] Another aspect of the present invention provides a method oftreating a condition which can be alleviated by antagonism of an EP₄receptor, which method comprises administering to a patient in need oftreatment an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

[0053] Conditions which can be alleviated by antagonism of an EP₄receptor are discussed above, and particularly include primary headachedisorders, most particularly migraines.

[0054] The present invention also provides methods of antagonizing EP₄receptors, in vitro or in vivo, comprising contacting a cell with aneffective amount of a compound of formula (I).

[0055] In some embodiments, the compounds described above may beselective as against antagonism of the other three EP receptors, i.e.EP₁, EP₂ and EP₃. This selectivity allows for targeting of the effect ofthe compounds of the invention, with possible benefits in the treatmentof certain conditions.

[0056] Definitions

[0057] Monodentate Groups

[0058] (i.e groups with one point of covalent attachment)

[0059] Alkyl: The term “alkyl” as used herein, pertains to a monovalentmoiety obtained by removing a hydrogen atom from a carbon atom of ahydrocarbon compound having from 1 to 7 carbon atoms (unless otherwisespecified), which may be aliphatic or alicyclic, and which may besaturated or unsaturated. Thus, the term “alkyl” includes thesub-classes alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cylcoalkynyl,etc., discussed below.

[0060] In the context of alkyl groups, the prefixes (e.g. C₁₋₄, C₁₋₇)denote the number of carbon atoms, or range of number of carbon atoms.For example, the term “C₁₋₄ alkyl” as used herein, pertains to an alkylgroup having from 1 to 4 carbon atoms. Examples of groups of alkylgroups include C₁₋₄ alkyl (“lower alkyl”) and C₁₋₇ alkyl. Note that thefirst prefix may vary according to other limitations; for example, forunsaturated alkyl groups, the first prefix must be at least 2; forcyclic alkyl groups, the first prefix must be at least 3; etc.

[0061] Examples of saturated alkyl groups include, but are not limitedto, methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl (C₅), hexyl(C₆) and heptyl (C₇).

[0062] Examples of saturated linear alkyl groups include, but are notlimited to, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl (C₄),n-pentyl (amyl) (C₅), n-hexyl (C₆), and n-heptyl (C₇).

[0063] Examples of saturated branched alkyl groups include iso-propyl(C₃), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄), iso-pentyl (C₅),and neo-pentyl (C₅).

[0064] Alkenyl: The term “alkenyl” as used herein, pertains to an alkylgroup having one or more carbon-carbon double bonds. Examples of groupsof alkenyl groups include C₂₋₄ alkenyl and C₂₋₇ alkenyl. Examples ofalkenyl groups include, but are not limited to, ethenyl (vinyl,—CH═CH₂), 1-propenyl (—CH═CH—CH₃), 2-propenyl (allyl, —CH—CH═CH₂),isopropenyl (1-methylvinyl, —C(CH₃)═CH₂), butenyl (C₄), pentenyl (C₅),and hexenyl (C₆).

[0065] Alkynyl: The term “alkynyl” as used herein, pertains to an alkylgroup having one or more carbon-carbon triple bonds. Examples of groupsof alkynyl groups include C₂₋₄ alkynyl and C₂₋₇ alkynyl. Examples ofalkynyl groups include, but are not limited to, ethynyl (ethinyl, —C≡CH)and 2-propynyl (propargyl, —CH₂—C≡CH).

[0066] Cycloalkyl: The term “cycloalkyl” as used herein, pertains to analkyl group which is also a cyclyl group; that is, a monovalent moietyobtained by removing a hydrogen atom from an alicyclic ring atom of acarbocyclic ring of a carbocyclic compound, which carbocyclic ring maybe saturated or unsaturated, which moiety has from 3 to 7 carbon atoms(unless otherwise specified), including from 3 to 7 ring atoms. Thus,the term “cycloalkyl” includes the sub-classes cycloalkyenyl andcycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms. Examplesof groups of cycloalkyl groups include C₃₋₇ cycloalkyl.

[0067] Examples of cycloalkyl groups include, but are not limited to,those derived from:

[0068] saturated monocyclic hydrocarbon compounds:

[0069] cyclopropane (C₃), cyclobutane (C₄), cyclopentane (C₅),cyclohexane (C₆), cycloheptane (C₇), methylcyclopropane (C₄),dimethylcyclopropane (C₅), methylcyclobutane (C₅), dimethylcyclobutane(C₆), methylcyclopentane (C₆), dimethylcyclopentane (C₇),methylcyclohexane (C₇);

[0070] unsaturated monocyclic hydrocarbon compounds:

[0071] cyclopropene (C₃), cyclobutene (C₄), cyclopentene (C₅),cyclohexene (C₆), methylcyclopropene (C₄), dimethylcyclopropene (C₅),methylcyclobutene (C₅), dimethylcyclobutene (C₆), methylcyclopentene(C₆), dimethylcyclopentene (C₇), methylcyclohexene (C₇);

[0072] Heterocyclyl: The term “heterocyclyl” as used herein, pertains toa monovalent moiety obtained by removing a hydrogen atom from a ringatom of a heterocyclic compound, which moiety has from 3 to 20 ringatoms (unless otherwise specified), of which from 1 to 10 are ringheteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of whichfrom 1 to 4 are ring heteroatoms.

[0073] In this context, the prefixes (e.g. C₃₋₂₀, C₃₋₇, C₅₋₆, etc.)denote the number of ring atoms, or range of number of ring atoms,whether carbon atoms or heteroatoms. For example, the term “C₅₋₆heterocyclyl” as used herein, pertains to a heterocyclyl group having 5or 6 ring atoms. Examples of groups of heterocyclyl groups include C₃₋₂₀heterocyclyl, C₅₋₂₀ heterocyclyl, C₃₋₁₅ heterocyclyl, C₅₋₁₅heterocyclyl, C₃₋₁₂ heterocyclyl, C₅₋₁₂ heterocyclyl, C₃₋₁₀heterocyclyl, C₅₋₁₀ heterocyclyl, C₃₋₇ heterocyclyl, C₅₋₇ heterocyclyl,and C₅₋₆ heterocyclyl.

[0074] Examples of monocyclic heterocyclyl groups include, but are notlimited to, those derived from:

[0075] N₁: aziridine (C₃), azetidine (C₄), pyrrolidine(tetrahydropyrrole) (C₅), pyrroline (e.g., 3-pyrroline,2,5-dihydropyrrole) (C₅), 2H-pyrrole or 3H-pyrrole (isopyrrole,isoazole) (C₅), piperidine (C₆), dihydropyridine (C₆),tetrahydropyridine (C₆), azepine (C₇);

[0076] O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅),oxole (dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆), dihydropyran(C₆), pyran (C₆), oxepin (C₇);

[0077] S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene)(C₅), thiane (tetrahydrothiopyran) (C₆), thiepane (C₇);

[0078] O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);

[0079] O₃: trioxane (C₆);

[0080] N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅),imidazoline (C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);

[0081] N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅),tetrahydroisoxazole (C₅), dihydroisoxazole (C₅), morpholine (C₆),tetrahydrooxazine (C₆), dihydrooxazine (C₆), oxazine (C₆);

[0082] N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);

[0083] N₂O₁: oxadiazine (C₆);

[0084] O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,

[0085] N₁O₁S₁: oxathiazine (C₆).

[0086] Aryl: The term “aryl” as used herein, pertains to a monovalentmoiety obtained by removing a hydrogen atom from an aromatic ring atomof an aromatic compound, which moiety has from 3 to 20 ring atoms(unless otherwise specified). Preferably, each ring has from 5 to 7 ringatoms.

[0087] In this context, the prefixes (e.g. C₃₋₂₀, C₅₋₇, C₅₋₆, etc.)denote the number of ring atoms, or range of number of ring atoms,whether carbon atoms or heteroatoms. For example, the term “C₅₋₆ aryl”as used herein, pertains to an aryl group having 5 or 6 ring atoms.Examples of groups of aryl groups include C₃₋₂₀ aryl, C₅₋₂₀ aryl, C₅₋₁₅aryl, C₅₋₁₂ aryl, C₅₋₁₀ aryl, C₅₋₇ aryl, C₅₋₆ aryl, C₅ aryl, and C₆aryl.

[0088] The ring atoms may be all carbon atoms, as in “carboaryl groups”.Examples of carboaryl groups include C₃₋₂₀ carboaryl, C₅₋₂₀ carboaryl,C₅₋₁₅ carboaryl, C₅₋₁₂ carboaryl, C₅₋₁₀ carboaryl, C₅₋₇ carboaryl, C₅₋₆carboaryl, C₅ carboaryl, and C₆ carboaryl.

[0089] Examples of carboaryl groups include, but are not limited to,those derived from benzene (i.e. phenyl) (C₆), naphthalene (C₁₀),azulene (C₁₀), anthracene (C₁₄), phenanthrene (C₁₄), naphthacene (C₁₈),and pyrene (C₁₆)

[0090] Examples of aryl groups which comprise fused rings, at least oneof which is an aromatic ring, include, but are not limited to, groupsderived from indane (e.g., 2,3-dihydro-1H-indene) (C₉), indene (C₉),isoindene (C₉), tetraline (1,2,3,4-tetrahydronaphthalene (C₁₀),acenaphthene (C₁₂), fluorene (C₁₃), phenalene (C₁₃), acephenanthrene(C₁₅), and aceanthrene (C₁₆).

[0091] Alternatively, the ring atoms may include one or moreheteroatoms, as in “heteroaryl groups”. Examples of heteroaryl groupsinclude C₃₋₂₀ heteroaryl, C₅₋₂₀ heteroaryl, C₅₋₁₅ heteroaryl, C₅₋₁₂heteroaryl, C₅₋₁₀ heteroaryl, C₅₋₇ heteroaryl, C₅₋₆ heteroaryl, C₅heteroaryl, and C₆ heteroaryl.

[0092] Examples of monocyclic heteroaryl groups include, but are notlimited to, those derived from:

[0093] N₁: pyrrole (azole) (C₅), pyridine (azine) (C₆);

[0094] O₁: furan (oxole) (C₅);

[0095] S₁: thiophene (thiole) (C₅);

[0096] N₁O₁: oxazole (C₅), isoxazole (C₅), isoxazine (C₆);

[0097] N₂O₁: oxadiazole (furazan) (C₅);

[0098] N₃O₁: oxatriazole (C₅);

[0099] N₁S₁: thiazole (C₅), isothiazole (C₅);

[0100] N₂: imidazole (1,3-diazole) (C₅), pyrazole (1,2-diazole) (C₅),pyridazine (1,2-diazine) (C₆), pyrimidine (1,3-diazine) (C₆), pyrazine(1,4-diazine) (C₆);

[0101] N₃: triazole (C₅), triazine (C₆); and,

[0102] N₄: tetrazole (C₅).

[0103] Examples of heteroaryl groups which comprise fused rings,include, but are not limited to:

[0104] C₉ (with 2 fused rings) derived from benzofuran (O₁),isobenzofuran (O₁), indole (N₁), isoindole (N₁), indolizine (N₁),indoline (N₁), isoindoline (N₁), purine (N₄) (e.g., adenine, guanine),benzimidazole (N₂), indazole (N₂), benzoxazole (N₁O₁), benzisoxazole(N₁O₁), benzodioxole (O₂), benzofurazan (N₂O₁), benzotriazole (N₃),benzothiofuran (S₁), benzothiazole (N₁S₁), benzothiadiazole (N₂S);

[0105] C₁₀ (with 2 fused rings) derived from chromene (O₁), isochromene(O₁), chroman (O₁), isochroman (O₁), benzodioxan (O₂), quinoline (N₁),isoquinoline (N₁), quinolizine (N₁), benzoxazine (N₁O₁), benzodiazine(N₂), pyridopyridine (N₂), quinoxaline (N₂), quinazoline (N₂), cinnoline(N₂), phthalazine (N₂), naphthyridine (N₂), pteridine (N₄);

[0106] C₁₁ (with 2 fused rings) derived from benzodiazepine (N₂);

[0107] C₁₃ (with 3 fused rings) derived from carbazole (N₁),dibenzofuran (O₁), dibenzothiophene (S₁), carboline (N₂), perimidine(N₂), pyridoindole (N₂); and,

[0108] C₁₄ (with 3 fused rings) derived from acridine (N₁), xanthene(O₁), thioxanthene (S₁), oxanthrene (O₂), phenoxathiin (O₁S₁), phenazine(N₂), phenoxazine (N₁O₁), phenothiazine (N₁S₁), thianthrene (S₂),phenanthridine (N₁), phenanthroline (N₂), phenazine (N₂).

[0109] If a heteroaryl or heterocyclyl group contains a nitrogen ringatom, this ring atom, where possible, may be in a oxidised state, as anN-oxide.

[0110] R³ is defined above as an optionally substituted C₆ aryl grouplinked to a further optionally substituted C₆ aryl group, wherein ifboth C₆ aryl groups are benzene rings there may be an oxygen bridgebetween the two rings, bound adjacent the link on both rings. Thus, ifboth C₆ aryl groups are benzene rings, then R³ can be optionallysubtitued biphenyl:

[0111] or optionally substituted dibenzofuran:

[0112] If one of the C₆ aryl groups is a C₆ heteroaryl group, thenexamples of R³ include, but are not limited to (not showing optionalsubstitution):

[0113] The above groups, whether alone or part of another substituent,may themselves optionally be substituted with one or more groupsselected from themselves, the additional monodentate substituents listedbelow and alkoxylene.

[0114] Halo: —F, —Cl, —Br, and —I.

[0115] Hydroxy: —OH.

[0116] Ether: —OR, wherein R is an ether substituent, for example, aC₁₋₇ alkyl group (also referred to as a C₁₋₇ alkoxy group, discussedbelow), a C₃₋₂₀ heterocyclyl group (also referred to as a C₃₋₂₀heterocyclyloxy group), or a C₅₋₂₀ aryl group (also referred to as aC₅₋₂₀ aryloxy group), preferably a C₁₋₇ alkyl group.

[0117] C₁₋₇ alkoxy: —OR, wherein R is a C₁₋₇ alkyl group. Examples ofC₁₋₇ alkoxy groups include, but are not limited to, —OMe (methoxy), —OEt(ethoxy), —O(nPr) (n-propoxy), —O(iPr) (isopropoxy), —O(nBu) (n-butoxy),—O(sBu) (sec-butoxy), —O(iBu) (isobutoxy), and —O(tBu) (tert-butoxy).

[0118] Oxo (keto, -one): ═O.

[0119] Thione (thioketone): ═S.

[0120] Imino (imine): ═NR, wherein R is an imino substituent, forexample, hydrogen, C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or aC₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇ alkyl group. Examples ofimino groups include, but are not limited to, ═NH, ═NMe, ═NEt, and ═NPh.

[0121] Formyl (carbaldehyde, carboxaldehyde): —C(═O)H.

[0122] Acyl (keto): —C(═O)R, wherein R is an acyl substituent, forexample, a C₁₋₇ alkyl group (also referred to as C₁₋₇ alkylacyl or C₁₋₇alkanoyl), a C₃₋₂₀ heterocyclyl group (also referred to as C₃₋₂₀heterocyclylacyl), or a C₅₋₂₀ aryl group (also referred to as C₅₋₂₀arylacyl), preferably a C₁₋₇ alkyl group. Examples of acyl groupsinclude, but are not limited to, —C(═O)CH₃ (acetyl), —C(═O)CH₂CH₃(propionyl), —C(═O)C(CH₃)₃ (t-butyryl), and —C(═O)Ph (benzoyl, phenone).

[0123] Carboxy (carboxylic acid): —C(═O)OH.

[0124] Thiocarboxy (thiocarboxylic acid): —C(═S)SH.

[0125] Thiolocarboxy (thiolocarboxylic acid): —C(═O)SH.

[0126] Thionocarboxy (thionocarboxylic acid): —C(═S)OH.

[0127] Imidic acid: —C(═NH)OH.

[0128] Hydroxamic acid: —C(═NOH)OH.

[0129] Ester (carboxylate, carboxylic acid ester, oxycarbonyl):—C(═O)OR, wherein R is an ester substituent, for example, a C₁₋₇ alkylgroup, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably aC₁₋₇ alkyl group. Examples of ester groups include, but are not limitedto, —C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh.

[0130] Acyloxy (reverse ester): —OC(═O)R, wherein R is an acyloxysubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples ofacyloxy groups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂ Ph.

[0131] Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide):—C(═O)NR¹R², wherein R¹ and R² are independently amino substituents, asdefined for amino groups. Examples of amido groups include, but are notlimited to, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃, and—C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R², togetherwith the nitrogen atom to which they are attached, form a heterocyclicstructure as in, for example, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, and piperazinocarbonyl.

[0132] Acylamido (acylamino): —NR¹C(═O)R², wherein R¹ is an amidesubstituent, for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇alkyl group, and R² is an acyl substituent, for example, a C₁₋₇ alkylgroup, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferablyhydrogen or a C₁₋₇ alkyl group. Examples of acylamide groups include,but are not limited to, —NHC(═O)CH₃, —NHC(═O)CH₂CH₃, and —NHC(═O) Ph. R¹and R² may together form a cyclic structure, as in, for example,succinimidyl, maleimidyl, and phthalimidyl:

[0133] Thioamido (thiocarbamyl): —C(═S)NR¹R², wherein R¹ and R² areindependently amino substituents, as defined for amino groups. Examplesof thioamido groups include, but are not limited to, —C(═S)NH₂,—C(═S)NHCH₃, —C(═S)N(CH₃)₂, and —C(═S)NHCH₂CH₃.

[0134] Ureido: —N(R¹)CONR²R³ wherein R² and R³ are independently aminosubstituents, as defined for amino groups, and R¹ is a ureidosubstituent, for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇alkyl group. Examples of ureido groups include, but are not limited to,—NHCONH₂, —NHCONHMe, —NHCONHEt, —NHCONMe₂, —NHCONEt₂, —NMeCONH₂,—NMeCONHMe, —NMeCONHEt, —NMeCONMe₂, and —NMeCONEt₂.

[0135] Guanidino: —NH—C(═NH)NH₂.

[0136] Tetrazolyl: a five membered aromatic ring having four nitrogenatoms and one carbon atom,

[0137] Amino: —NR¹R², wherein R¹ and R² are independently aminosubstituents, for example, hydrogen, a C₁₋₇ alkyl group (also referredto as C₁₋₇ alkylamino or di-C₁₋₇ alkylamino), a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably H or a C₁₋₇ alkyl group, or, inthe case of a “cyclic” amino group, R¹ and R², taken together with thenitrogen atom to which they are attached, form a heterocyclic ringhaving from 4 to 8 ring atoms. Amino groups may be primary (—NH₂),secondary (—NHR¹), or tertiary (—NHR¹R²), and in cationic form, may bequaternary (—⁺NR¹R²R³). Examples of amino groups include, but are notlimited to, —NH₂, —NHCH₃, —NHC(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh.Examples of cyclic amino groups include, but are not limited to,aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino,and thiomorpholino.

[0138] Amidine (amidino): —C(═NR)NR₂, wherein each R is an amidinesubstituent, for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀ aryl group, preferably H or a C₁₋₇ alkylgroup. Examples of amidine groups include, but are not limited to,—C(═NH)NH₂, —C(═NH)NMe₂, and —C(═NMe)NMe₂.

[0139] Nitro: —NO₂.

[0140] Nitroso: —NO.

[0141] Cyano (nitrile, carbonitrile): —CN.

[0142] Sulfhydryl (thiol, mercapto): —SH.

[0143] Thioether (sulfide): —SR, wherein R is a thioether substituent,for example, a C₁₋₇ alkyl group (also referred to as a C₁₋₇ alkylthiogroup), a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably aC₁₋₇ alkyl group. Examples of C₁₋₇ alkylthio groups include, but are notlimited to, —SCH₃ and —SCH₂CH₃.

[0144] Disulfide: —SS—R, wherein R is a disulfide substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group (also referred to herein as C₁₋₇alkyl disulfide). Examples of C₁₋₇ alkyl disulfide groups include, butare not limited to, —SSCH₃ and —SSCH₂CH₃.

[0145] Sulfine (sulfinyl, sulfoxide): —S(═O)R, wherein R is a sulfinesubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples ofsulfine groups include, but are not limited to, —S(═O)CH₃ and—S(═O)CH₂CH₃.

[0146] Sulfone (sulfonyl): —S(═O)₂R, wherein R is a sulfone substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group, including, for example, afluorinated or perfluorinated C₁₋₇ alkyl group. Examples of sulfonegroups include, but are not limited to, —S(═O)₂CH₃ (methanesulfonyl,mesyl), —S(═O)₂CF₃ (triflyl), —S(═O)₂CH₂CH₃ (esyl), —S(═O)₂C₄F₉(nonaflyl), —S(═O)₂CH₂CF₃ (tresyl), —S(═O)₂CH₂CH₂NH₂ (tauryl), —S(═O)₂Ph(phenylsulfonyl, besyl), 4-methylphenylsulfonyl (tosyl),4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl (brosyl),4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and5-dimethylamino-naphthalen-1-ylsulfonate (dansyl).

[0147] Sulfinic acid (sulfino): —S(═O)OH, —SO₂H.

[0148] Sulfonic acid (sulfo): —S(═O)₂OH, —SO₃H.

[0149] Sulfinate (sulfinic acid ester): —S(═O)OR; wherein R is asulfinate substituent, for example, a C₁₋₇alkyl group, aC₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkylgroup. Examples of sulfinate groups include, but are not limited to,—S(═O)OCH₃ (methoxysulfinyl; methyl sulfinate) and —S(═O)OCH₂CH₃(ethoxysulfinyl; ethyl sulfinate).

[0150] Sulfinyloxy: —OS(═O)R, wherein R is a sulfinyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or aC₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Examples of sulfinyloxygroups include, but are not limited to, —OS(═O)CH₃ and —OS(═O)CH₂CH₃.

[0151] Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide):—S(═O)NR¹R², wherein R¹ and R² are independently amino substituents, asdefined for amino groups. Examples of sulfamyl groups include, but arenot limited to, —S(═O)NH₂, —S(═O)NH(CH₃), —S(═O)N(CH₃)₂,—S(═O)NH(CH₂CH₃), —S(═O)N(CH₂CH₃)₂, and —S(═O)NHPh.

[0152] Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide):—S(═O)₂NR¹R², wherein R¹ and R² are independently amino substituents, asdefined for amino groups. Examples of sulfonamido groups include, butare not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂,—S(═O)₂NH(CH₂CH₃), —S(═O)₂N(CH₂CH₃)₂, and —S(═O)₂NHPh.

[0153] Sulfonamino: —NR¹S(═O)₂R, wherein R¹ is an amino substituent, asdefined for amino groups, and R is a sulfonamino substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇ alkyl group. Examples of sulfonamino groupsinclude, but are not limited to, —NHS(═O)₂CH₃ and —N(CH₃)S(═O)₂C₆H₅.

[0154] Sulfinamino: —NR¹S(═O)R, wherein R¹ is an amino substituent, asdefined for amino groups, and R is a sulfinamino substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of sulfinamino groupsinclude, but are not limited to, —NHS(═O)CH₃ and —N(CH₃)S(═O)C₆H₅.

[0155] As already mentioned, the above described groups may besubstituted, and particular examples include, but are not limited to,C₃₋₂₀ aryl-C₁₋₇ alkyl groups, which include benzyl (phenylmethyl,PhCH₂—), benzhydryl (Ph₂CH—), trityl (triphenylmethyl, Ph₃C—), phenethyl(phenylethyl, Ph-CH₂CH₂—), styryl (Ph-CH═CH—) and cinnamyl(Ph-CH═CH—CH₂—).

[0156] Bidentate groups

[0157] (i.e. groups with two points of covalent attachment; linkinggroups)

[0158] Alkylene: The term “C₁₋₃ alkylene”, as used herein, pertains to abidentate moiety obtained by removing two hydrogen atoms from each oftwo different carbon atoms, of a linear hydrocarbon compound having from1 to 3 carbon atoms, which may be saturated or unsaturated. Thus, theterm “alkylene” includes the sub-classes alkenylene and alkynylene.

[0159] In this context, the prefix C₁₋₃ denotes the number of carbonatoms, or range of number of carbon atoms.

[0160] Examples of saturated C₁₋₃ alkylene groups include —CH₂—(methylene), —CH₂CH₂— (ethylene) and —CH₂CH₂CH₂— (propylene).

[0161] Examples of unsaturated C₁₋₃ alkylene groups (which may be termed“C₂₋₃ alkenylene” or “C₂₋₃ alkynylene”, as appropriate) include —CH═CH—(vinylene), —CH═CH—CH₂—, —CH₂—CH═CH—, —C≡C—, —C≡C—CH₂— and —CH₂—C≡C—.

[0162] The C₁₋₃ alkylene group may be substituted by any monodentatesubstituent described above.

[0163] Alkoxylene: The term “alkoxylene,” as used herein, pertains to abidentate group of formula —O(CH₂)_(n)O—, where n is 1 or 2.

[0164] Includes Other Forms

[0165] Unless otherwise specified, included in the above are the wellknown ionic, salt, solvate, and protected forms of these substituents.For example, a reference to carboxylic acid (—COOH) also includes theanionic (carboxylate) form (—COO⁻), a salt or solvate thereof, as wellas conventional protected forms. Similarly, a reference to an aminogroup includes the protonated form (—N⁺HR¹R²), a salt or solvate of theamino group, for example, a hydrochloride salt, as well as conventionalprotected forms of an amino group.

[0166] Similarly, a reference to a hydroxyl group also includes theanionic form (—O⁻), a salt or solvate thereof, as well as conventionalprotected forms of a hydroxyl group.

[0167] Isomers, Salts, Solvates and Protected Forms

[0168] Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric,tautomeric, conformational, or anomeric forms, including but not limitedto, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- andexo-forms; R—, S—, and meso-forms; D- and L-forms; d- and l-forms; (+)and (−) forms; keto-, enol-, and enolate-forms; syn- and anti-forms;synclinal- and anticlinal-forms; α- and β-forms; axial and equatorialforms; boat-, chair-, twist-, envelope-, and halfchair-forms; andcombinations thereof, hereinafter collectively referred to as “isomers”(or “isomeric forms”).

[0169] Note that, except as discussed below for tautomeric forms,specifically excluded from the term “isomers”, as used herein, arestructural (or constitutional) isomers (i.e. isomers which differ in theconnections between atoms rather than merely by the position of atoms inspace). For example, a reference to a methoxy group, —OCH₃, is not to beconstrued as a reference to its structural isomer, a hydroxymethylgroup, —CH₂OH. Similarly, a reference to ortho-chlorophenyl is not to beconstrued as a reference to its structural isomer, meta-chlorophenyl.However, a reference to a class of structures may well includestructurally isomeric forms falling within that class (e.g. C₁₋₇alkylincludes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, andtert-butyl; methoxyphenyl includes ortho-, meta-, andpara-methoxyphenyl).

[0170] The above exclusion does not pertain to tautomeric forms, forexample, keto-, enol-, and enolate-forms, as in, for example, thefollowing tautomeric pairs: keto/enol (illustrated below),imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.

[0171] Note that specifically included in the term “isomer” arecompounds with one or more isotopic substitutions. For example, H may bein any isotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

[0172] Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including (wholly or partially)racemic and other mixtures thereof. Methods for the preparation (e.g.asymmetric synthesis) and separation (e.g. fractional crystallisationand chromatographic means) of such isomeric forms are either known inthe art or are readily obtained by adapting the methods taught herein,or known methods, in a known manner.

[0173] Unless otherwise specified, a reference to a particular compoundalso includes ionic, salt, solvate, and protected forms of thereof, forexample, as discussed below.

[0174] It may be convenient or desirable to prepare, purify, and/orhandle a corresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66,1-19 (1977).

[0175] For example, if the compound is anionic, or has a functionalgroup which may be anionic (e.g. —COOH may be —COO⁻), then a salt may beformed with a suitable cation. Examples of suitable inorganic cationsinclude, but are not limited to, alkali metal ions such as Na⁺ and K⁺,alkaline earth cations such as Ca²⁺ and Mg²⁺, and other cations such asAl⁺³. Examples of suitable organic cations include, but are not limitedto, ammonium ion (i.e. NH₄ ⁺) and substituted ammonium ions (e.g. NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

[0176] If the compound is cationic, or has a functional group which maybe cationic (e.g. —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

[0177] Examples of suitable organic anions include, but are not limitedto, those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

[0178] It may be convenient or desirable to prepare, purify, and/orhandle a corresponding solvate of the active compound. The term“solvate” is used herein in the conventional sense to refer to a complexof solute (e.g., active compound, salt of active compound) and solvent.If the solvent is water, the solvate may be conveniently referred to asa hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate,etc.

[0179] It may be convenient or desirable to prepare, purify, and/orhandle the active compound in a chemically protected form. The term“chemically protected form” is used herein in the conventional chemicalsense and pertains to a compound in which one or more reactivefunctional groups are protected from undesirable chemical reactionsunder specified conditions (e.g. pH, temperature, radiation, solvent,and the like). In practice, well known chemical methods are employed toreversibly render unreactive a functional group, which otherwise wouldbe reactive, under specified conditions. In a chemically protected form,one or more reactive functional groups are in the form of a protected orprotecting group (also known as a masked or masking group or a blockedor blocking group). By protecting a reactive functional group, reactionsinvolving other unprotected reactive functional groups can be performed,without affecting the protected group; the protecting group may beremoved, usually in a subsequent step, without substantially affectingthe remainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley andSons, 1999).

[0180] A wide variety of such “protecting”, “blocking”, or “masking”methods are widely used and well known in organic synthesis. Forexample, a compound which has two nonequivalent reactive functionalgroups, both of which would be reactive under specified conditions, maybe derivatized to render one of the functional groups “protected,” andtherefore unreactive, under the specified conditions; so protected, thecompound may be used as a reactant which has effectively only onereactive functional group. After the desired reaction (involving theother functional group) is complete, the protected group may be“deprotected” to return it to its original functionality.

[0181] For example, a hydroxy group may be protected as an ether (—OR)or an ester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl,benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; atrimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester(—OC(═O)CH₃, —OAc).

[0182] For example, an aldehyde or ketone group may be protected as anacetal (R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which thecarbonyl group (>C═O) is converted to a diether (>C(OR)₂), by reactionwith, for example, a primary alcohol. The aldehyde or ketone group isreadily regenerated by hydrolysis using a large excess of water in thepresence of acid.

[0183] For example, an amine group may be protected, for example, as anamide (—NRCO—R) or a urethane (—NRCO—OR), for example, as: an acetamide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH—Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH—Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH—Bpoc), as a 9-fluorenylmethoxy amide(—NH—Fmoc), as a 6-nitroveratryloxy amide (—NH—Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), as a2(phenylsulfonyl)ethyloxy amide (—NH-Psec); or, in suitable cases (e.g.,cyclic amines), as a nitroxide radical (>N—O).

[0184] For example, a carboxylic acid group may be protected as an esterfor example, as: an C₁₋₇ alkyl ester (e.g., a methyl ester; a t-butylester); a C₁₋₇ haloalkyl ester (e.g., a C₁₋₇ trihaloalkyl ester); atriC₁₋₇ alkylsilyl-C₁₋₇ alkyl ester; or a C₅₋₂₀ aryl-C₁₋₁₇ alkyl ester(e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example,as a methyl amide.

[0185] For example, a thiol group may be protected as a thioether (—SR),for example, as: a benzyl thioether; an acetamidomethyl ether(—S—CH₂NHC(═O)CH₃).

[0186] The term “treatment”, as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g. in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, amelioration of the condition,and cure of the condition. Treatment as a prophylactic measure (i.e.prophylaxis) is also included.

[0187] The term “therapeutically-effective amount”, as used herein,pertains to that amount of an active compound, or a material,composition or dosage form comprising an active compound, which iseffective for producing some desired therapeutic effect, commensuratewith a reasonable benefit/risk ratio, when administered in accordancewith a desired treatment regimen. Suitable dose ranges will typically bein the range of from 0.01 to 20 mg/kg/day, preferably from 0.1 to 10mg/kg/day.

[0188] Compositions and their Administration

[0189] Compositions may be formulated for any suitable route and meansof administration. Pharmaceutically acceptable carriers or diluentsinclude those used in formulations suitable for oral, rectal, nasal,topical (including buccal and sublingual), vaginal or parenteral(including subcutaneous, intramuscular, intravenous, intradermal,intrathecal and epidural) administration. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. Such methods includethe step of bringing into association the active ingredient with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

[0190] For solid compositions, conventional non-toxic solid carriersinclude, for example, pharmaceutical grades of mannitol, lactose,cellulose, cellulose derivatives, starch, magnesium stearate, sodiumsaccharin, talcum, glucose, sucrose, magnesium carbonate, and the likemay be used. The active compound as defined above may be formulated assuppositories using, for example, polyalkylene glycols, acetylatedtriglycerides and the like, as the carrier. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, etc, an active compound as defined above and optionalpharmaceutical adjuvants in a carrier, such as, for example, water,saline aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnon-toxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, sorbitan monolaurate,triethanolamine oleate, etc. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, 20th edition, pub.Lippincott, Williams & Wilkins, 2000. The composition or formulation tobe administered will, in any event, contain a quantity of the activecompound(s) in an amount effective to alleviate the symptoms of thesubject being treated.

[0191] Dosage forms or compositions containing active ingredient in therange of 0.25 to 95% with the balance made up from non-toxic carrier maybe prepared.

[0192] For oral administration, a pharmaceutically acceptable non-toxiccomposition is formed by the incorporation of any of the normallyemployed excipients, such as, for example, pharmaceutical grades ofmannitol, lactose, cellulose, cellulose derivatives, sodiumcrosscarmellose, starch, magnesium stearate, sodium saccharin, talcum,glucose, sucrose, magnesium carbonate, and the like. Such compositionstake the form of solutions, suspensions, tablets, pills, capsules,powders, sustained release formulations and the like. Such compositionsmay contain 1%-95% active ingredient, more preferably 2-50%, mostpreferably 5-8%.

[0193] Parenteral administration is generally characterized byinjection, either subcutaneously, intramuscularly or intravenously.Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol, ethanolor the like. In addition, if desired, the pharmaceutical compositions tobe administered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like, such as for example, sodium acetate, sorbitan monolaurate,triethanolamine oleate, triethanolamine sodium acetate, etc.

[0194] The percentage of active compound contained in such parentalcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject. However,percentages of active ingredient of 0.1% to 10% in solution areemployable, and will be higher if the composition is a solid which willbe subsequently diluted to the above percentages. Preferably, thecomposition will comprise 0.2-2% of the active agent in solution.

[0195] Acronyms

[0196] For convenience, many chemical moieties are represented usingwell known abbreviations, including but not limited to, methyl (Me),ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), sec-butyl(sBu), iso-butyl (iBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl(cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph),methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).

[0197] For convenience, many chemical compounds are represented usingwell known abbreviations, including but not limited to, methanol (MeOH),ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), etheror diethyl ether (Et₂O), acetic acid (AcOH), dichloromethane (methylenechloride, DCM), acetonitrile (ACN), trifluoroacetic acid (TFA),dimethylformamide (DMF), tetrahydrofuran (THF), and dimethylsulfoxide(DMSO).

[0198] General Synthesis Methods

[0199] Compounds of the invention wherein R⁵ is of formula (II):

[0200] may be synthesised from the analogous compound of the inventionwherein R⁵ is carboxy, by reaction with a compound of formula 1:

[0201] in basic conditions, preferably aided by a coupling agent, forexample, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0202] Compounds of the invention wherein R⁵ is of formula (III):

[0203] may be synthesized from a compound of formula 2:

[0204] by reaction with a compound of formula 3:

[0205] wherein X is either OH or halo, where if X is OH, the use ofbasic conditions and a coupling agent is preferred.

[0206] Compounds of formulae (I) and 2, or where the group -A-R¹ ispresent as a precursor or protected form, may be represented ascompounds of formula 4:

[0207] where R⁶ is -A-R⁵ or its precursor or protected form. Theprotecting groups used may be conventional, or the group may beresin-bound. If Y is —(CH₂)_(n)—O— or —(CH₂)_(n)—S—, then thesecompounds can be synthesised from compounds of formula 5:

[0208] by one of two possible routes.

[0209] In the first route, a compound of formula 6:

R³—X′H  Formula 6

[0210] , where X′ is S or O, is coupled to a compound of formula 5 usingthe Mitsunobu reaction, for example by treatment with triphenylphosphine (Ph₃P) and diisopropylazodicarboxylate (DIAD).

[0211] The second route is a two stage route, the first stage being theMitsunobu coupling of a compound of formula 7a:

Hal-Ar¹—X′H  Formula 7a

[0212] wherein Ar¹ is the first C₆ aryl component of R³ and Hal is I orBr followed by a Suzuki coupling of a compound of formula 8a (orequivalent ester of formula 8c):

Ar²—B(OH)₂  Formula 8a

[0213] wherein Ar² is the second C₆ aryl component of R³. The Suzukicoupling may be achieved using, for example,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) as thepalladium catalyst.

[0214] This route may also be ‘reversed’ such that the Mitsunobucoupling is of a boronic acid of formula 7b (or preferably equivalentester of formula 7c):

HX′—Ar¹—B(OH)₂  Formula 7b

[0215] wherein Ar¹ is the first C₆ aryl component of R³, followed by aSuzuki coupling of a compound of formula 8b:

Ar²—Hal  Formula 8b

[0216] wherein Ar² is the second C₆ aryl component of R³ and Hal is I orBr.

[0217] If the compound of formula 7b or 7c is not readily available thena compound of formula 7d:

HX′—Ar¹—Br  Formula 7d

[0218] may be coupled, followed by conversion of the bromo group to therequired boronic acid or ester.

[0219] Compounds of formula 4 where Y is —(CH₂)_(n)—NH— can also besynthesized from compounds of formula 5. In one method, the alcohols offormula 5 are oxidized to the corresponding aldehyde, for example usingthe Dess-Martin reagent, followed by reductive coupling to an amine,which may be of formula 6′:

R³—NH₂  Formula 6′

[0220] or of formula 7a′, 7b′ or 7c′:

Hal-Ar¹—NH₂  Formula 7a′

H₂N—Ar¹—B(OH)₂  Formula 7b′

[0221] for subsequent Suzuki coupling. The reductive coupling can becarried out using sodium cyanoborohydride.

[0222] In another method, the alcohol of formula 5 is converted to thecorresponding halide, using a halogenating reagent, for exampleconversion to chlorine using 4-methyl-benzene sulfonyl chloride,followed by coupling to an amine which may be of formula 6′, or offormula 7a′, 7b′ or 7c′ for subsequent Suzuki coupling. The aminecoupling is carried out in the presence of potassium iodide, orequivalent reagents. This method can also be used to couple alcohols andthiols of formulae 6, 7a, 7b and 7d, where X′ is O or S.

[0223] Compounds of formula 4:

[0224] where Y is —C(═O)—NR^(N1)— may be synthesised from a compound offormula 9:

[0225] by reaction with a amine of formula 10:

[0226] in basic conditions, preferably with the aid of a coupling agent.

[0227] Compounds of formula 9:

[0228] may be derived from compounds of formula 11:

[0229] by oxidation, for example, using Jones' reagent.

[0230] Compounds of formula (I) where A is a single bond, and R⁵ iscarboxy, and compounds where the group —Y—R³ is present as a precursoror protected form, may be represented as compounds of formula 12:

[0231] where R⁷ is —Y—R³ or its precursor or protected form. Thesecompounds may be synthesised from compounds of formula 13:

[0232] by treatment with n-butyllithium, followed by carbon dioxide atlow temperatures.

[0233] In a similar fashion, compounds of formula 2 where A is a singlebond, and R⁵ is carboxy, and compounds where the group —Y—R³ is presentas a precursor or protected form, may be represented as compounds offormula 14:

[0234] where R⁷ is —Y—R³ or its precursor or protected form. Thesecompounds may be synthesised from compounds of formula 13:

[0235] by treatment with a strong base and sulphur dioxide at lowtemperatures, followed by amination.

[0236] Compounds of formula (I) where A is a —C₂H₄—, and R⁵ is carboxy,and compounds where the group —Y—R³ is present as a precursor orprotected form, may be represented as compounds of formula 15:

[0237] where R⁷ is —Y—R³ or its precursor or protected form. Thesecompounds may be synthesised from compounds of formula 16:

[0238] by hydrogenation, using a palladium catalyst.

[0239] Compounds of formula 16 may be synthesised from compounds offormula 17:

[0240] by the Wittig coupling of an acetic ester, using, for example,triethylphosphonoacetate as the Wittig reagent, followed by hydolysisunder alkaline conditions, e.g. lithium hydroxide in a suitable solvent,e.g. aqueous alcohol.

[0241] Compounds of formula 17 may also be used to synthesise compoundsof formula 18:

[0242] where R² and R⁷ are as defined above. The reaction proceeds via acyano intermediate which may be obtained by treating compounds offormula 17 with hydroxylamine to form the oxime derivative, which can bedehydrated to the cyano compound with, for example,2-chloro-1,3-dimethylimidazolium chloride in the presence of a base. Thecyano intermediate can be converted into compounds of formula 18 bytreatment with sodium azide, in the presence of a base.

[0243] Compounds where Y is —(CH₂)_(n)—S(═O)— and —(CH₂)_(n)—S(═O)₂— maybe obtained from the corresponding compound where Y is —(CH₂)_(n)—S— byoxidation with a peracid, for example 3-chloro-benzenecarboperoxoicacid.

[0244] Compounds where Y is —(CH₂)_(n)—NR^(N1)— may be obtained from thecorresponding compound where Y is —(CH₂)_(n)—NH— by direction alkylationby R^(N1)I, in the presence of a weak base.

[0245] The starting materials described above are generally commerciallyavailable or synthesisable using known methods. For example, example 22Abelow describes a method of synthesizing 2-substitued furans.

[0246] Some of the reaction steps described above may be carried outusing resins, as is shown in the examples.

[0247] Preferences

[0248] The following preferences may be combined with one another, andmay be different for each aspect of the present invention.

[0249] R² is preferably selected from H or an optionally substitutedC₁₋₃ alkyl group, more preferably H, methyl, CF₃ or iso-propyl, and mostpreferably R² is a a methyl group.

[0250] Y is preferably —(CH₂)_(n)—X—, and n is preferably 1. X ispreferably O, S or NH, with NH being the most preferred. In someembodiments the preferred option for Y is —CH₂—O—.

[0251] If Y is —C(═O)NR^(N2)—, then R^(N2) is preferably selected fromH, and optionally substituted C₁₋₄ alkyl, in particular Me.

[0252] The C₆ aryl groups of R³ are preferably independently selectedfrom those derived from benzene and heteroaryl groups, where theheteroatom or heteroatoms are nitrogen. Most preferred are C₆ arylgroups derived from benzene, pyridine and 1,3-pyrimidine. It is furtherpreferred that either both C₆ aryl groups are derived from benzene orthat one group is derived from benzene and the other from pyridine or1,3-pyrimidine, with pyridine being preferred, especially as the arylgroup furthest from the furan core.

[0253] If both C₆ aryl groups are derived from benzene, it is preferredthat there is not an oxygen bridge between the two rings, bound adjacentthe link on both rings, i.e. that R₃ is optionally substituted biphenylrather than optionally substituted dibenzofuranyl.

[0254] If one or more of the C₆ aryl groups is derived from pyridine,then it is preferred that the nitrogen ring atom is adjacent the linkbetween the two rings that make up the R³ group.

[0255] If one or more of the C₆ aryl groups is derived from1,3-pyrimidine, then it is preferred that the link between the two ringsthat make up the R³ group is between the two nitrogen atoms.

[0256] It is further preferred that that the single bond joining the twoC₆ aryl groups is in the 4-position of the ring bound to Y. Thus,4-phenyl-phenyl is preferred to 3-phenyl-phenyl; dibenzofuran-3-yl ispreferred to di-benzofuran-2-yl, 4-pyridin-2-yl-phenyl is preferred to3-pyridin-2-yl-phenyl and 6-phenyl-pyridin-3-yl is preferred to6-phenyl-pyridin-2-yl:

[0257] Both C₆ aryl groups of R³ are optionally substituted, although itis preferred that only the C₆ aryl group not bound to Y is substituted.

[0258] Preferred substituents on the C₆ aryls of R³ include, but are notlimited to: optionally substituted C₁₋₇ alkyl groups, more preferablymethyl and substituted C₁₋₄ alkyl groups, e.g. —CF₃, CH₂OH; C₁₋₇ alkoxygroups, more preferably C₁₋₄ alkoxy groups, e.g. —OMe, —OCF₃, —OEt,—OCHF₂; C₁₋₇ thioether group, more preferably C₁₄ thioether group, e.g.—SMe; amino groups, optionally substituted by one or two C₁₋₄ alkylgroups, e.g. —NMe₂; halo groups, more preferably —F or —Cl; cyano;alkoxylene groups, more preferably —O—CH₂—O—; C₁₋₄ acyl groups, morepreferably —C(═O)Me.

[0259] The preferred location for a substituent on the C₆ aryl group notbound to Y is para to the bond between the two C₆ aryl groups, with themeta position being less preferred. Therefore, if R³ is 4-phenyl-phenyl,the substituent is preferably at the 4′-position.

[0260] In some embodiments of the present invention A is preferably asingle bond, whereas in other embodiments A is preferably a C₁₋₃alkylene group. In particular, when R⁵ is carboxy, A is more preferablya C₁₋₃ alkylene group, with vinylene being most preferred.

[0261] R⁵ is preferably either:

[0262] (i) a group of formula (II):

[0263] (ii) a group of formula (III):

[0264] with a group of formula (II) being more preferred.

[0265] The above preference for R⁵ is particularly applicable when R² ismethyl and Y is —CH₂—O—.

[0266] Where R⁵ is of formula (II) of (III), R is preferably selectedfrom an optionally substituted C₅₋₂₀ aryl group, and an optionallysubstituted C₅₋₂₀ aryl-C₁₋₇ alkyl group, wherein the C₁₋₇ alkyl group ismore preferably methyl. In these groups the C₅₋₂₀ aryl group ispreferably a heteroaryl group, itself preferably having a singlearomatic ring. Such groups may preferably be substituted with C₁₋₄ alkylgroups, such as methyl and hydroxy. Thus, preferred R groups include,but are not limited to: phenyl; benzyl; 3,5, dimethyl-isoxazol-4-yl;thiophen-2-yl; 5-methyl-pyridin-yl; and 4-hydroxy-phenyl.

[0267] If R in formula (II) or (III) is a C₁₋₇ alkyl group, it is morepreferably a C₁₋₄ alkyl group, for example methyl or propyl.

[0268] Particularly preferred compounds of the present inventioninclude:

[0269] 4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (4);

[0270]N-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(5);

[0271]N-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-C-phenyl-methanesulfonamide(6);

[0272]N-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-methanesulfonamide(7);

[0273] Propane-1-sulfonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(8);

[0274] 3,5-Dimethyl-isoxazole-4-sulfonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(9);

[0275] Thiophene-2-sulfonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(10);

[0276] 5-Methyl-pyridyl-2-sulfonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(11);

[0277]4-Aminomethyl-N-[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(trifluoroacetate salt) (12);

[0278]4-Hydroxy-N-[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(13);

[0279] 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18);

[0280]N-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(19);

[0281] 4-(4′-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (21);

[0282]N-[4-(4′-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(22);

[0283] 4-(4′-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylicacid (24);

[0284] 5-Benzenesulfonylaminocarbonyl-2-methyl-furan-3-carboxylic acid(4′-methoxy-biphenyl-4-yl)-amide (25);

[0285] 4-(4′-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (27);

[0286]4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylicacid (28);

[0287] [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid(31);

[0288] 4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-aceticacid (32);

[0289] 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionic acid(37);

[0290]N-{3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzenesulfonamide (38);

[0291]3-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionicacid (39);

[0292]N-{3-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzenesulfonamide (40);

[0293] 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid(42);

[0294]3-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylicacid (43);

[0295] 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acidbenzoylamide (46);

[0296] 4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonicacid benzoylamide (49);

[0297] 4-(Dibenzofuran-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid(50);

[0298]4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylicacid (53);

[0299]4-[6-(4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylicacid (56);

[0300] 4-(4′-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (57);

[0301] 3-Morpholin-4-yl-propane-1-sulphonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(59);

[0302]N-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide(60);

[0303] 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acidbutyryl-amide (61);

[0304] 4-(Biphenyl-4-yloxymethyl)-5-methyl -furan-2-sulfonic acidphenylacetyl-amide (62);

[0305] 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid(3,5-dimethyl-isoxazole-4-carbonyl)-amide (63);

[0306] 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid(thiophene-2-carbonyl)-amide (64);

[0307] 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid(3-methoxy-propionyl)-amide (65);

[0308] 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid(pyridin-3-yl-acetyl)-amide (66);

[0309] 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid(pyridine-4-carbonyl)-amide (67);

[0310] 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid(pyridine-3-carbonyl)-amide (68);

[0311] 4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonicacid (3,5-dimethyl-isoxazole-4-carbonyl)-amide (69);

[0312] 4-[2-(Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid(72);

[0313]4-[2-(4′-Methoxy-biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylicacid (73);

[0314] 4-[2-(Dibenzofuran-3-yloxy)-ethyl]-5-methyl-furan-2-carboxylicacid (74);

[0315] 4-(Biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (77);

[0316] 4-(Dibenzofuran-2-yloxymethyl)-furan-2-carboxylic acid (78);

[0317] 4-(4′-Cyano-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (79);

[0318] 4-(4′-Methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid(80);

[0319] 4-(Dibenzofuran-3-yloxymethyl)-furan-2-carboxylic acid (81);

[0320] 4-(Biphenyl-4-yloxymethyl)-5-isopropyl-furan-2-carboxylic acid(85);

[0321]5-Isopropyl-4-(4′-methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (86);

[0322] 4-(Dibenzofuran-3-yloxymethyl)-5-isopropyl-furan-2-carboxylicacid (87);

[0323] 4-(Biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylicacid (90);

[0324] 4-(Biphenyl-3-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylicacid (91);

[0325]4-(Dibenzofuran-2-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylic acid(92);

[0326]4-(4′-Cyano-biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylicacid (93);

[0327]4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylicacid (94);

[0328]4-(Dibenzofuran-3-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylic acid(95);

[0329]4-(3′,4′-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (96);

[0330] 4-(4′-Ethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (98);

[0331] 4-(2′-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (99);

[0332]4-(2′,6′-Difluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (100);

[0333]5-Methyl-4-(2′-trifluoromethyl-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (102);

[0334] 4-(3′-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (104);

[0335]5-Methyl-4-(2′-methylsulfanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (105);

[0336]4-(3′,4′-Dimethoxy-biphenyl-3-yloxymethyl)-5-methyl-furan-2-carboxylicacid (108);

[0337]5-Methyl-4-(3′-trifluoromethyl-biphenyl-3-yloxymethyl)-furan-2-carboxylicacid (109);

[0338]4-(4′-Hydroxymethyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (110);

[0339]5-Methyl-4-(4′-methylsulfanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (111);

[0340] 4-(3′-Hydroxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (112);

[0341]4-(4′-Dimethylamino-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (113);

[0342]5-Methyl-4-(4′-trifluoromethoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (114);

[0343]5-Methyl-4-(2′-trifluoromethoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (115);

[0344] 4-(3′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (116);

[0345] 4-(3′-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (117);

[0346] 4-(4′-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (118);

[0347]N-4-(4′-Methoxy-biphen-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-dimethylaminosulphonamide(122);

[0348] 4-(2′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (126);

[0349]N-[4-(2′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(127);

[0350]4-(4′-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (129);

[0351]N-[4-(4′-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(130);

[0352] 3,5-Dimethyl-isoxazole-4-sulfonic acid[4-(4′-difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(131);

[0353]N-{4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-benzenesulfonamide(132);

[0354] 3,5-Dimethyl-isoxazole-4-sulfonic acid{4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-amide(133);

[0355]N-{4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide(134);

[0356]N-{4-[4-(5-Methoxy-1-oxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-benzenesulfonamide(135);

[0357] 5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carboxylicacid (137);

[0358]N-[5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carbonyl]-benzenesulfonamide(138);

[0359]4-(2′,4′-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (140);

[0360]N-[4-(2′,4′-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(141);

[0361] 3,5-Dimethyl-isoxazole-4-sulfonic acid[4-(2′,4′-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(142);

[0362]4-(4′-Methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (144);

[0363]N-[4-(4′-Methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(145);

[0364] 3,5-Dimethyl-isoxazole-4-sulfonic acid[4-(4′-methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(146);

[0365] 5-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-1H-tetrazole(149);

[0366]4-(4′-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carboxylicacid (153);

[0367]N-[4-(4′-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide(154);

[0368]N-[4-(4′-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(155);

[0369]N-[4-(4′-Difluoromethoxy-biphenyl-4-sulfinylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide(156);

[0370]N-[4-(4′-Difluoromethoxy-biphenyl-4-sulfonylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide(156a);

[0371] 4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid(160);

[0372]N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(161);

[0373]N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide(162);

[0374]N-(4-{[4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carbonyl)-2-methyl-benzenesulfonamide(167);

[0375]4-[(4′-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carboxylicacid (171);

[0376]N-{4-[(4′-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carbonyl}-benzenesulfonamide(172);

[0377]N-{4-[(4′-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide(173);

[0378] 3,5-Dimethyl-isoxazole-4-sulfonic acid{4-[(4′-difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carbonyl}-amide(174);

[0379]4-{[(4′-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylicacid (176); and

[0380]N-(4-{[(4′-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carbonyl)-2-methyl-benzenesulfonamide(177).

[0381] The selectivity of the compound for antagonising EP₄ receptorsover the other EP receptors (i.e. EP₁, EP₂, EP₃) can be quantified bydividing the Ki for EP₄ (see below) by the Ki for the other EP receptors(see below). The resulting ratio is preferably 10 or more, morepreferably 100 or more.

Synthesis Examples

[0382] General Experimental Details

[0383] All reactions were carried out under an inert atmosphere ofnitrogen.

[0384] Where products were purified by flash chromatography thestationary phase used was silica gel for chromatography, 0.035 to 0.070mm (220 to 440 mesh) (e.g. Fluka silica gel 60). An applied pressure ofnitrogen of ˜10 psi was used to accelerate column elution. Thin layerchromatography (TLC) was carried out on aluminium foil plates coatedwith silica gel containing a fluorescent indicator (254 nm) (e.g. Fluka60778).

[0385] Petroleum ether refers to that fraction with a boiling point of40-60° C.

[0386] Organic solutions were dried over magnesium sulphate unlessotherwise specified.

[0387] PS-TsCl refers to Polystyrene scavenger resin (loading 1.97mmol/g)—Argonaut Technologies (P/N 800277)

[0388] Preparative HPLC System

[0389] Preparative HPLC was carried out on a C18-reverse-phase column(10×2.1 cm i.d Genesis column with 7 μm particle size), eluting with agradient of acetonitrile (containing 0.1% trifluoroacetic acid) andwater (containing 0.1% trifluoroacetic acid) at a flow rate of 5 ml/min.UV detection at 230 nm was used unless otherwise stated.

[0390] LC/MS Systems

[0391] The Liquid Chromatography Mass Spectroscopy (LC/MS) systems usedare as follows.

[0392] LC/MS System A:

[0393] Mass Spectrometer—Platform LC with electrospray source operatingin positive and negative Ion mode. HP1100 system running at 2.0 mL/min,200 μL/min split to the ESI source with inline HP1100 DAD detection andSEDEX ELS detection.

[0394] Mobile Phase

[0395] A) Water 0.1% Formic Acid

[0396] B) acetonitrile 0.1% Formic Acid Gradient Time Flow (min)(mL/min) % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 5 95 5.00 2.0 5 955.50 2.0 95 5

[0397] Column—Luna 3u C18(2) 30×4.6 mm

[0398] LC/MS System B:

[0399] Mass Spectrometer—Platform II with electrospray source operatingin negative ion mode. HP1100 system running at 2.0 mL/min, 200 μL/minsplit to the ESI source with inline HP1100 DAD detection and SEDEX ELSdetection.

[0400] Mobile Phase

[0401] A) Water 0.1% Diethylamine

[0402] B) acetonitrile Gradient Time Flow (min) (mL/min) % A % B 0.002.0 95 5 0.50 2.0 95 5 4.00 2.0 5 95 4.50 2.0 5 95 5.00 2.0 95 5 20.002.0 95 5

[0403] Column—XTerra MS C18 3.5 μm 4.6×30 mm

[0404] LCMS System C:

[0405] Mass Spectrometer—Finnigan TSQ700 with electrospray sourceoperating in negative ion mode. HP1050 system running at 2.0 mL/min, 200μL/min split to the ESI source with inline HP1050 Single wavelength UVdetector at 254 nm.

[0406] Mobile Phase

[0407] A) Water 0.1% Diethylamine

[0408] B) acetonitrile Gradient Time Flow (min) (mL/min) % A % B 0.002.0 95 5 1.00 2.0 95 5 15.00 2.0 5 95 17.00 2.0 5 95 18.00 2.0 95 520.00 2.0 95 5

[0409] Column—XTerra MS C18 3.5 μm 4.6×30 mm

[0410] LC/MS System D:

[0411] Mass Spectrometer—Finnigan TSQ700 with electrospray sourceoperating in positive or negative ion mode. HP1050 system running at 2.0mL/min, 200 μL/min split to the ESI source with inline HP1050 SingleWavelength UV detector at 254 nm.

[0412] Mobile Phase

[0413] A) Water 0.1% formic Acid

[0414] B) acetonitrile 0.1% formic Acid Gradient Time Flow (min)(mL/min) % A % B 0.00 2.0 95 5 1.00 2.0 95 5 15.00 2.0 5 95 17.00 2.0 595 18.00 2.0 95 5 20.00 2.0 95 5

[0415] Column—Higgins Clipius C18 5 μm 100×3.0 mm

[0416]¹H NMR system

[0417] The ¹H NMR spectra were recorded on a Varian Unity Inova 400,which operates at 400 MHz for ¹H. It is equipped with a 5 mm inversedetection triple resonance probe for detection of ¹H. The magnetic fieldis provided by a 9.4 Tesla Oxford instruments super-conducting magnet.The host computer is a Sun Microsystems SunBlade 1000 workstation.D₆-dimethylsulphoxide was used as solvent unless stated otherwise.Tetramethylsilane was used as internal standard. Coupling constants arereported in Hz.

Example 1 Synthesis of4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(4), 4-(Dibenzofuran-3-yloxymethyl)-5-methyl-furan-2-carboxylic acid(50), 4-(Dibenzofuran-2-yloxymethyl)-5-methyl-furan-2-carboxylic acid(56) and 4-(4′-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (57)

[0418] (a) 3-(tert-Butyl-diphenyl-silanyloxymethyl)-2-methyl-furan (2)

[0419] A stirred solution of (2-methyl-3-furan-3-yl)-methanol (1)(31.87g) in N,N-dimethylformamide (250 mL) was treated simultaneously witht-butyldiphenylsilyl chloride (94 g) and imidazole (24 g) and stirringcontinued for 2 hours at room temperature. The reaction mixture wastreated with 1.0 M hydrochloric acid (500 mL), and extracted withdiethyl ether (3×500 mL). The combined organic extracts were washedsuccessively with 1.0 M hydrochloric acid (500 mL), saturated sodiumhydrogen carbonate (500 mL), then dried and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with mixtures ofdiethyl ether in hexane (1:9 to 9:1 by volume) to give compound 2 as aclear oil (67.6 g).

[0420] (b)4-(tert-Butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carboxylicacid (3)

[0421] A solution of3-(tert-Butyl-diphenyl-silanyloxymethyl)-2-methyl-furan (2) (30.0 g) intetrahydrofuran (75 mL) was cooled to −78° C. with stirring and treateddrop-wise with a solution of n-butyllithium (2.5 M in hexanes, 71 mL)over 10 mins. The cooling bath was removed for 0.5 hours and thenreplaced. A large excess of solid carbon dioxide was added and themixture allowed to warm to ambient temperature. The reaction mixture wasacidified, with 1.0 M hydrochloric acid to pH 2 and extracted intodiethyl ether (3×500 mL). The combined extracts were washed successivelywith 1.0 M hydrochloric acid (500 mL), water (500 mL), dried andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with mixtures of diethyl ether in pentane (1:5 to 5:1 by volume)to give compound 3 as a yellow oil (10.36 g). LC/MS System A: R_(t)=4.33mins, m/z (ES⁻)=393 (M⁻ for C₂₃H₂₆O₄Si).

[0422] (c)4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(4)

[0423] (i) 2-Chlorotrityl chloride resin (1 g of nominal loading 1.3mmol/g) was swelled with dichloromethane (20 mL). After draining, asolution of4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carboxylicacid (3) (0.512 g) and diisopropylethylamine (0.91 mL) indichloromethane (10 mL) was added and the mixture was shaken at ambienttemperature for 16 hours. The resin was drained, washed sequentiallywith dichloromethane/triethylamine/methanol (20:1:3 by volume) (3×25mL), dichloromethane (3×25 mL), N,N-dimethylformamide (2×25 mL),dichloromethane (6×25 mL), and diethyl ether (2×25 mL) and then dried at40° C. in vacuo.

[0424] (ii) The loaded resin from (i) (2.47 g) was swelled intetrahydrofuran (15 mL), then treated tetrabutylammonium fluoride (12.8mL of a 1 M solution in tetrahydrofuran) and shaken at room temperaturefor 16 hours. The resin was drained, washed sequentially withtetrahydrofuran/water (1:1 by volume), tetrahydrofuran,N,N-dimethylformamide, dichloromethane, diethyl ether, and then dried at40° C. in vacuo.

[0425] (iii) The loaded resin (2.83 g) from (ii) was swelled intetrahydrofuran (15 mL), and then treated with a solution of4-hydroxy-4′-methoxydiphenyl (2.93 g) and triphenylphosphine (3.48 g) intetrahydrofuran (20 mL), followed by the addition ofdiisopropylazodicarboxylate (2.96 g). The mixture was shaken at roomtemperature for 16 hours. The resin was drained, washed sequentiallywith tetrahydrofuran/water (1:1 by volume), tetrahydrofuran,N,N-dimethylformamide, dichloromethane, and then dried at 45° C. invacuo. The resin was treated with dichloromethane/trifluoroacetic acid(19:1 by volume) (20 mL) for 20 mins and the solution drained from theresin. This procedure was repeated. The combined solutions wereconcentrated in vacuo and the residue recrystallised from ethanol toafford compound 4 as a white solid (0.42 g). LC/MS System C: R_(t)=4.00mins, m/z (ES⁻)=337 (M⁻ for C₂₀H₁₈O₅).

[0426] (d) 4-(Dibenzofuran-3-yloxymethyl)-5-methyl-furan-2-carboxylicacid (50)

[0427] Compound (50) was prepared by adapting the procedure of Example1(c). LC/MS System B: R_(t)=1.79 mins, m/z (ES⁻)=321 ((M−H) forC₁₉H₁₄O₅).

[0428] (e) 4-(Dibenzofuran-2-yloxymethyl)-5-methyl-furan-2-carboxylicacid (56)

[0429] Compound (56) was prepared by adapting the procedure of Example1(c). LC/MS System B: R_(t)=1.76 mins, m/z (ES⁻)=321 ((M−H) forC₁₉H₁₄O₅).

[0430] (f)4-(4′-Cyano-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(57)

[0431] Compound (57) was prepared by adapting the procedure of Example1(c). LC/MS System B: R_(t)=1.72 mins, m/z (ES⁻)=332 ((M−H) forC₂₀H₁₅NO₄).

Example 2A Synthesis ofN-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(5)

[0432]

[0433] A stirred solution of4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(4) (250 mg) in dichloromethane (50 mL) was treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (142 mg),4-(N,N-dimethylamino)pyridine (2 mg) and benzenesulfonamide (232 mg).After 16 hours the reaction mixture was concentrated in vacuo, theresidue dissolved in ethyl acetate (200 mL) and washed successively withwater (20 mL), 1.0 M hydrochloric acid (20 mL), saturated sodiumhydrogen carbonate solution (20 mL), brine (20 mL), dried andconcentrated in vacuo. The crude product was purified by HPLC to affordcompound 5 as a white solid (30 mg). LC/MS System D: R_(t)=5.45 mins,m/z (ES⁻)=476 (M⁻ for C₂₆H₂₃NO₆S).

[0434] By adapting the procedure of Example 2A and using the appropriatesulphonamide there were prepared Examples 2B to 2G:

Example 2BN-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-C-phenyl-methanesulfonamide(6)

[0435]

[0436] LC/MS System C: R_(t) 5.37 mins, m/z (ES⁻)=490 (M⁻for C₂₇H₂₅NO₆S)

Example 2CN-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-methanesulfonamide(7)

[0437]

[0438] LC/MS System C: R_(t)=4.50 mins, m/z (ES⁻)=414 (M⁻ forC₂₁H₂₁NO₆S).

Example 2D Propane-1-sulfonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(8)

[0439]

[0440] LC/MS System C: R_(t)=4.78 mins, m/z (ES⁻)=442 (M⁻ forC₂₃H₂₅NO₆S).

Example 2E 3,5-Dimethyl-isoxazole-4-sulfonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(9)

[0441]

[0442] LC/MS System C: R_(t)=4.91 mins, m/z (ES⁻)=495 (M⁻ forC₂₅H₂₄N₂O₇S).

Example 2F Synthesis of Thiophene-2-sulfonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(10)

[0443]

[0444] LC/MS System C: R_(t)=4.94 mins, m/z (ES⁻)=482 (M⁻ forC₂₄H₂₁NO₆S₂).

Example 2G 5-Methyl-pyridyl-2-sulfonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(11)

[0445]

[0446] LC/MS System D: R_(t)=10.09 mins, m/z (ES⁺)=493 (MH⁺ forC₂₆H₂₄NO₆S).

Example 2H Synthesis of4-Aminomethyl-N-[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamidetrifluoroacetate (12)

[0447]

[0448] 4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (4) (50 mg) was reacted with (4-sulphamoyl-benzyl)-carbamic acidtert-butyl ester (85 mg) in an analogous manner to that described inExample 2A. The intermediate tert-butyl carbamate was hydrolysed with 1%trifluoroacetic acid/dichloromethane over 24 hours, then concentrated invacuo to give compound 12 as a white solid (10 mg). LC/MS System C:R_(t)=4.67 mins, m/z (ES⁻)=493 (M⁻ 1 for C₂₇H₂₆N₂O₆S).

Example 2I Synthesis of4-Hydroxy-N-[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(13)

[0449]

[0450] 4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (4) (50 mg) was reacted with acetic acid 4-sulphamoyl-phenyl ester(64 mg) in an analogous manner to that described in Example 2A. Theacetic ester intermediate was hydrolysed with sodium methoxide (80 mg)in a mixture of methanol (10 mL) and water (1 mL) for 1 hour. Thesolution was concentrated in vacuo then partitioned betweendichloromethane (10 mL) and water (10 mL). The organic layer was washedwith brine (10 mL), dried, filtered and concentrated in vacuo. The crudeproduct was purified by preparative HPLC (starting at 30% acetonitrileand increasing at a rate of 1% per minute up to 98% acetonitrile) togive compound 13 as a white solid (15 mg). LC/MS System C: R_(t)=3.50mins, m/z (ES⁻)=492 (M⁻ for C₂₆H₂₃N₂O₇S).

Example 3 Synthesis of4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18)

[0451] (a) Triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14)

[0452] Triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane was preparedfrom (2-methyl-furan-3-yl)-methanol (1)(24.22 g) in an analogous mannerto that described in Example 1 to give compound 14 as a clear oil (54.0g).

[0453] (b) 5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-carboxylicacid methyl ester (15)

[0454] A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane(14) (10.0 g) in tetrahydrofuran (300 mL) was cooled to −78° C. withstirring was treated drop-wise with sec-butyllithium (3.0 M incyclohexane, 37 mL). After 1 hour the reaction mixture was treateddrop-wise with a solution of methyl chloroformate (5.2 g) intetrahydrofuran (30 mL) over 10 mins and stirring was continued at −78°C. for 1 hour. The reaction mixture was then treated with saturatedammonium chloride solution (300 mL) and allowed to warm to ambienttemperature. The two layers were separated and the organic phase washedwith brine (300 mL), dried and concentrated in vacuo. The residue waspurified by flash chromatography eluting with ethyl acetate/pentane (1:9by volume) to give compound 15 as a clear oil.

[0455] (c) 4-Hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester(16)

[0456] A stirred solution of5-methyl-4-triisopropylsilanyloxymethyl-furan-2-carboxylic acid methylester (15) (5.2 g) in tetrahydrofuran (200 mL) was treated withtetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 3.2 mL)and stirring continued for 16 hours. The reaction mixture wasconcentrated in vacuo and the residue taken up in ethyl acetate (350 mL)and washed with water (150 mL). The aqueous phase was re-extracted withethyl acetate (2×100 mL). The combined extracts were dried, concentratedin vacuo and the residue was purified by flash chromatography elutingwith ethyl acetate/pentane (1:1 by volume) to give compound 16 as ayellow oil.

[0457] (d) 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acidmethyl ester (17)

[0458] A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acidmethyl ester (16) (1g) in anhydrous tetrahydrofuran (20 mL) was cooledto 0° C. under a nitrogen atmosphere. 4-Hydroxybiphenyl (3 g) andtriphenylphosphine (4.61 g) were added and the mixture was treated withdiisopropylazodicarboxylate (3.46 mL) dropwise. The mixture was stirredat 0° C. for 10 min then cooling was removed and the mixture stirred fora further 3 hours. The solvent was removed in vacuo and the residue waspartitioned between ethyl acetate (50 mL) and water (100 mL). Theorganic phase was separated, dried and evaporated. The residue waspurified by flash chromatography, eluting with pentane /ethyl acetate9:1 by volume to give a mixture of the title compound and4-hydroxybiphenyl (1.8 g). This material was purified further by flashchromatography eluting with dichloromethane/methanol 99:1 by volume togive compound 17 as a white solid (200 mg). LCMS System A: R_(t)=4.2mins.

[0459] (e) 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(18)

[0460] 1 M Aqueous lithium hydroxide (18 mL) was added to solution of4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester(17) (1 g) in tetrahydrofuran/methanol (2:1 by volume, 100 mL) and themixture stirred at room temperature for 5 h. The solvent was removed invacuo, the residue dissolved in water (20 mL) and the solution acidifiedto pH6 with aqueous dilute hydrochloric acid. The mixture was evaporatedto dryness and the residue was purified by HPLC to afford compound 18 asa white solid (210 mg). LC/MS System B: R_(t)=4.80 mins, m/z=307 ((M−1)for C₁₉H₁₆O₄).

Example 4 Synthesis ofN-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(19)

[0461]

[0462] Compound (19) was prepared by adapting the procedure of Example2A. LC/MS System D: R_(t)=9.18 mins, m/z (ES⁻)=446 (M⁻ for C₂₅H₂₁NO₅S).

Example 5 Synthesis of4-(4′-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(21)

[0463] (a) 4-(4-Iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acidmethyl ester (20)

[0464] A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acidmethyl ester (16) (1.14 g) in tetrahydrofuran (15 mL) was cooled to 0°C. with stirring and treated with 4-iodophenol (4.6 g),triphenylphosphine (5.5 g) and diisopropylazodicarboxylate (4.2 g).After 10 minutes the cooling bath was removed. After 3 hours thereaction mixture was concentrated in vacuo and taken up in ethyl acetate(100 mL) and washed successively with water (100 mL), 1.0 M aqueoussodium hydroxide solution (100 mL), dried and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate/hexane (1:4 by volume) to give compound 20 as a white solid(1.58 g).

[0465] (b)4-(4′-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(21)

[0466] A stirred mixture of4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester(20) (0.26 g), 4-acetylphenylboronic acid (0.15 g),N,N-dimethylformamide (30 mL), potassium acetate (0.26 g) and[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (40 mg) was heated at 90° C. over night. Thereaction mixture was concentrated in vacuo, dissolved in ethyl acetate(30 mL) and washed successively with water (30 mL), brine (30 mL), driedand concentrated in vacuo. The residue was dissolved in a mixture oftetrahydrofuran/methanol (2:1 by volume) (30 mL) and 1.0 M aqueouslithium hydroxide solution (6.78 mL) and stirred for 16 hours. Thereaction mixture was acidified to pH 2 using 0.1 M hydrochloric acid andextracted with ethyl acetate (3×25 mL). The extract was dried,concentrated in vacuo and the residue purified by HPLC to give compound21 as a white solid (50 mg). LC/MS System C: R_(t)=4.18 mins, m/z(ES⁻)=349 (M⁻ for C₂₁H₁₈O₅).

Example 6 Synthesis ofN-[4-(4′-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(22)

[0467]

[0468] Compound (22) was prepared by adapting the procedure of Example2A. LC/MS System D: R_(t)=9.87 mins, m/z (ES⁺)=490 (MH⁺ for C₂₇H₂₃NO₆S).

Example 7 Synthesis of4-(4′-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylic acid(24)

[0469] (a) 5-methyl-furan-2,4-dicarboxylic acid-2-methyl ester (23)

[0470] Jones' reagent (Prepared according to Fieser and Fieser, Reagentsfor Organic Synthesis, Volume 1, page 142, 1967) was added drop-wise toa stirred solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acidmethyl ester (16) (100 mg) in acetone (10 mL) until the orangecolouration just remained. Stirring was continued for a further 5 hoursthen the reaction mixture was diluted with diethyl ether (20 mL) andfiltered. The filtrate was dried and concentrated in vacuo to affordcompound 23 as a buff coloured solid.

[0471] (b)4-(4′-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylic acid(24)

[0472] To a solution of 5-methyl-furan-2,4-dicarboxylic acid-2-methylester (23) (100 mg) in N,N-dimethylformamide (3.0 mL) was addedO—(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (228 mg), diisopropylethylamine (0.56 mL) and4′-methoxy-biphenyl-4-ylamine (120 mg). The resulting solution wasstirred at room temperature for 2 hours. The reaction mixture wasdiluted with ethyl acetate (20 mL) and washed successively with water(2×20 mL), 0.1 M hydrochloric acid (20 mL), water (20 mL), saturatedsodium hydrogen carbonate (10 mL) and brine (10 mL). This solution wasdried and concentrated in vacuo. The residue (170 mg) was dissolved indichloromethane (5 mL), treated with triethylamine (0.3 mL) and ascavenger resin PS-TsCl (0.6 g) and the mixture shaken for 3 hours atroom temperature. The reaction mixture was filtered and concentratedin-vacuo. The residue was dissolved in methanol/tetrahydrofuran (1:3 byvolume) (20 mL), treated with 1.0 M aqueous lithium hydroxide solution(2.0 mL) and allowed to stir at room temperature for 4 hours. The pH ofthe reaction mixture was adjusted to between pH 4 and pH 5 by carefuladdition of 1.0 M hydrochloric acid (1.0 mL) and partly concentrated invacuo.

[0473] The residue was then partitioned between ethyl acetate (2×25 mL)and water (25 mL) and the combined organic extracts were washed withbrine (35 mL), dried (Na₂SO₄), and concentrated in vacuo affordedcompound 24 as beige solid (58 mg). LC/MS System D: R_(t)=7.23 mins, m/z(ES⁺)=351 (MH⁺ for C₂₀H₁₇NO₅).

Example 8 Synthesis of5-Benzenesulfonylaminocarbonyl-2-methyl-furan-3-carboxylic acid(4′-methoxy-biphenyl-4-yl)-amide (25)

[0474]

[0475] Compound 25 was synthesised from4-(4′-Methoxy-biphenyl-4-ylcarbamoyl)-5-methyl-furan-2-carboxylic acid(24) (35 mg) in an analogous manner to that described in Example 2A togive the title compound as a white solid (7 mg). LC/MS System A:R_(t)=3.86 mins, m/z (ES⁻)=489 (M−1 for C₂₆H₂₂N₂O₆S).

Example 9 Synthesis of4-(4′-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(27) and4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylicacid (28)

[0476] (a) 4-(4-Iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid(26)

[0477] A stirred solution of4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester(20) (2.7 g) in tetrahydrofuran (25 mL) was treated with a solution oflithium hydroxide (1.5 g) in water (2 mL). After 3 hours the reactionmixture was diluted with water and acidified to pH 2 with 1.0 Mhydrochloric acid. The white precipitate was filtered off and dried invacuo. The solid was triturated with ethyl acetate at 0° C. thencollected by filtration to give compound 26 as a white solid (1.83 g).LC/MS system A: R_(t)=1.74 min.

[0478] (b)4-(4′-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(27)

[0479] (i) 2-Chlorotrityl chloride resin (2.55 g of nominal loading 1.3mmol/g) was swelled with dichloromethane (20 mL). After draining, asolution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid(26) (1.18 g) and diisopropylethylamine (2.3 mL) in dichloromethane (30mL) was added and the mixture was shaken at room temperature for 72hours. The resin was drained, washed sequentially withdichloromethane/triethylamine/methanol (20:1:3 by volume) (3×30 mL),dichloromethane (6×30 mL), N,N-dimethylformamide (2×25 mL),dichloromethane (6×25 mL), and diethyl ether (2×25 mL) and dried at 40°C. in vacuo.

[0480] (ii) A stirred mixture of the resin from (i) (0.38 g),4-chlorophenylboronic acid (0.30 g),[1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (30 mg), potassium acetate (0.20 g) inN,N-dimethylformamide (15 mL) was heated at 40° C. for 48 hours. Theresin was drained, then washed sequentially with tetrahydrofuran/water(1:1 by volume), tetrahydrofuran, N,N-dimethylformamide,dichloromethane, diethyl ether and then dried at 45° C. in vacuo. Theresin was treated with dichloromethane/trifluoroacetic acid (19:1 byvolume) (20 mL) for 20 mins and the solution drained from the resin.This procedure was repeated. The combined solutions were concentrated invacuo and the residue purified by HPLC to afford compound 27 as a whitesolid (43 mg). LC/MS System D: R_(t)=8.83 mins, m/z (ES⁻)=341 (M⁻ forC₁₉H₁₅ClO₄).

[0481] (c)4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylicacid (28)

[0482] Compound 28 was synthesised from the resin from (i) in step (b)above and 3,4-methylenedioxyphenylboronic acid in an analogous manner tothat described in step (ii) above. LC/MS System C: R_(t)=4.60 mins, m/z(ES⁻)=351 (M⁻ for C₂₀H₁₆O₆).

Example 10 Synthesis of[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid (31) and4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid(32)

[0483] (a) (5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-aceticacid ethyl ester (29)

[0484] A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane(14) (5.0 g) in tetrahydrofuran (15 mL) was cooled to −78° C. withstirring. This solution was treated drop-wise with n-butyl lithium (2.5M in hexanes, 8.94 mL). The resulting solution was warmed to 0° C. andallowed to stand for 30 minutes after which a solution of dried zincchloride (3.04 g) in tetrahydrofuran (10 mL) was added and the resultingsolution allowed to stand for a further 1 hour at room temperature.Concurrently, a second reaction vessel was charged with tetrahydrofuran(10 mL), nickel(II) acetylacetonate (120 mg), and triphenylphosphine(122 mg) and cooled (−5° C.). Ethyl bromoacetate (1.03 mL) was added tothis mixture, followed by the addition of the previously preparedsolution of the furyl-zinc chloride. The resulting reaction mixture wasallowed to warm to room temperature then stirred for a further 16 hoursat room temperature. The reaction was quenched by the addition ofsaturated ammonium chloride solution (100 mL) and extracted with ethylacetate (3×150 mL). The combined organic extracts were successivelywashed with water (200 mL) and brine (250 mL), dried, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyusing a gradient elution (diethyl ether/petroleum ether (40-60°) 1:49 to1:25 by volume) to give compound 29 as a clear oil (1.44 g). LC/MSSystem A: R_(t)=5.16 min.

[0485] (b) (4-Hydroxymethyl-5-methyl-furan-2-yl)-acetic acid ethyl ester(30)

[0486] A solution of(5-methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-acetic acid ethylester (29) (0.5 g) in tetrahydrofuran (3.0 mL) was cooled to 0° C. withstirring and treated with tetrabutylammonium fluoride (1.0 M solution intetrahydrofuran, 2.82 mL) under argon. After 30 minutes, the resultingsolution was concentrated in-vacuo and partitioned between water (30 mL)and ethyl acetate (4×25 mL). The combined organic extracts were washedwith brine (50 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified by flash chromatography eluting with diethylether/petroleum ether (1:1 by volume) to give compound 30 as a clear oil(188 mg). LC/MS System A: R_(t)=2.34 mins.

[0487] (c) [4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid(31)

[0488] Compound (31) was prepared from compound (30) in an analagousmanner to the methods described in Examples 3(d) and 3(e). LC/MS SystemC: R_(t)=4.97 mins, m/z (ES⁻)=321 (M⁻ for C₂₀H₁₈O₄).

[0489] (d)[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acetic acid(32)

[0490] Compound (32) was prepared from compound (30) in an analagousmanner to the methods described in Examples 3(d) and 3(e). LC/MS SystemC: R_(t)=4.94 mins, m/z (ES⁻)=351 (M⁻ for C₂₁H₂₀O₅).

Example 11 Synthesis of3-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionic acid (37) andN-{3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzenesulfonamide (38)

[0491] (a) 5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-carbaldehyde(33)

[0492] A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane(14) (10 g) in tetrahydrofuran (250 mL) was cooled to −78° C. withstirring, and then sec-butyllithium (1.3 M in cyclohexane; 37.25 mL) wasadded drop-wise over 10 mins. After stirring for 45 mins at −78° C., thecooling bath was removed for a period of 15 mins then re-introduced. Asolution of N,N-dimethylformamide (14.4 mL) in tetrahydrofuran (25 mL)was added drop-wise and the resulting reaction mixture was stirred at−78° C. for a further 2 hours. The reaction mixture was allowed to warmto room temperature and then poured into saturated ammonium chloridesolution (150 mL). This mixture was extracted with diethyl ether (2×350mL), and the combined organic extracts were washed with water (500 mL)and brine (500 mL), dried, and concentrated in vacuo to give compound 33as an amber coloured oil. LC/MS System A: R_(t)=4.86 mins.

[0493] (b)3-(5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-acrylic acidethyl ester (34)

[0494] A stirred solution of5-methyl-4-triisopropylsilanyloxymethyl-furan-2-carbaldehyde (33) (10.6g) in tetrahydrofuran (25 mL) was treated with triethylphosphonoacatete(7.81 mL) and lithium hydroxide (1.65 g). The resulting mixture wasstirred for 16 hours then concentrated in vacuo and the residuepartitioned between water (100 mL) and diethyl ether (3×100 mL). Thecombined organic extracts were further washed with water (200 mL) andbrine (200 mL), then dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with diethylether/petroleum ether (1:40 by volume) to give compound 34 as a clearyellow oil (10.56 g). LC/MS System A: R_(t)=4.59 mins.

[0495] (c)3-(5-Methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-propionic acidethyl ester (35)

[0496] A solution of3-(5-methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-acrylic acidethyl ester (34) (1.0 g) in ethyl acetate (70 mL) was treated with 5%w/w palladium on carbon (350 mg) and hydrogenated at 1 atmosphere forexactly 1¼ hours at room temperature. The reaction mixture was filteredthrough filter-aid and then concentrated in vacuo to afford compound 35as a clear oil (1.05 g). LC/MS System A: R_(t)=5.52 mins.

[0497] (d) 3-(4-Hydroxymethyl-5-methyl-furan-2-yl)-propionic acid ethylester (36)

[0498] Compound (36) was prepared in the form of a clear oil fromcompound (35) by adapting the procedure described in Example 3(c). LC/MSSystem A: R_(t)=2.68 mins.

[0499] (e) 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionicacid (37)

[0500] To a stirred, cooled 0° C. solution, in tetrahydrofuran (2.5 mL),a solution of 3-(4-hydroxymethyl-5-methyl-furan-2-yl)-propionic acidethyl ester (36) (400 mg) in tetrahydrofuran (2.5 mL) was cooled to 0°C. and treated successively with triphenylphosphine (542 mg),biphenyl-4-ol (353 mg) and diisopropylazodicarboxylate (0.41 mL). Afterstirring for 10 mins at 0° C. the reaction mixture was allowed to warmto room temperature and then stirred for a further 16 hours. Thereaction mixture was concentrated in-vacuo then re-dissolved indichloromethane (15 mL) and treated with triethylamine (1.50 mL) and ascavenger resin PS-TsCl (2.5 g) and the mixture was shaken for 6 hoursat room temperature. The reaction mixture was purified by flashchromatography, eluting with a mixture of diethyl ether in petroleumether (40-60° C.) (7:93 by volume). The purified product (320 mg) wasdissolved in methanol/tetrahydrofuran (2:1 by volume) (18 mL), treatedwith 1.0 M aqueous lithium hydroxide solution (9 mL) and allowed to stirat room temperature for 6 hours. The pH of the reaction mixture wasadjusted to between pH4 and pH5 by the addition of 1.0 M hydrochloricacid (˜5.0 mL), then treated with saturated ammonium chloride (100 mL)and extracted with ethyl acetate (2×100 mL). The combined organicextracts were further washed with brine (35 mL), then dried (sodiumsulphate) and concentrated in vacuo. A sample of the crude product (50mg) was purified by HPLC to give compound 37 as white solid (25 mg).LC/MS System C: R_(t)=5.33 mins, m/z (ES⁻)=335 (M⁻ for C₂₁H₂₀O₄).

[0501] (f)N-{3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzenesulfonamide (38)

[0502] Compound (38) was prepared from compound (37) by the procedure ofExample 2A. LC/MS System C: R_(t)=5.82 mins, m/z (ES⁻)=475 (M⁻ forC₂₇H₂₅O₅S).

Example 12 Synthesis of3-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionicacid (39) andN-{3-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzenesulfonamide (40)

[0503] (a)3-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionicacid (39)

[0504] Compound (39) was prepared from compound (36) in an analogousmanner to that described in Example 11(e). LC/MS System C: R_(t)=5.31mins, m/z (ES⁻)=365 (M⁻ for C₂₂H₂₂O₅).

[0505] (b)N-{3-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-propionyl}-benzenesulfonamide (40)

[0506] Compound (40) was prepared from compound (39) by the procedure ofExample 2A. LC/MS System C: R_(t)=5.78 mins, m/z (ES⁻)=504 (M⁻ forC₂₈H₂₇NO₆S).

Example 13 Synthesis of3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylic acid (42) and3-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylicacid (43)

[0507] (a) 3-(4-Hydroxymethyl-5-methyl-furan-2-yl)-acrylic acid ethylester (41)

[0508] Compound (41) was prepared in the form of a yellow oil fromcompound (34) by adapting the procedure described in Example 3(c). LC/MSSystem A: R_(t)=2.82 mins.

[0509] (b) 3-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylicacid (42)

[0510] Compound (42) was prepared from compound (41) by adapting theprocedure of Example 11(e). LC/MS System C: R_(t)=4.91 mins, m/z(ES⁻)=333 (M⁻ for C₂₁H₁₈O₄).

[0511] (c)3-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-acrylicacid (43)

[0512] Compound (43) was prepared from compound (41) by adapting theprocedure of Example 11(e). LC/MS System C: R_(t)=4.85 mins, m/z(ES⁻)=363 (M⁻ for C₂₂H₂₀O₅).

Example 14A Synthesis of4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid benzoylamide(46)

[0513] (a) 3-(Biphenyl-4-yloxymethyl)-2-methyl-furan (44)

[0514] A solution of (2-methyl-furan-3-yl)-methanol (1)(5.0 g) indiethyl ether (75 mL) was cooled to 0° C. with stirring and treated withtriphenylphosphine (12.85 g) and biphenyl-4-ol (7.59 g). The resultingsolution was then treated drop-wise with diisopropylazodicarboxylate(9.75 mL). After stirring for 10 minutes at 0° C. the reaction mixturewas allowed to warm to room temperature and then stirred for a further 3hours. The reaction mixture was then filtered and concentrated in vacuo.The residue was purified by flash chromatography, eluting with diethylether/petroleum ether (1:19 by volume), to give compound 44 as a whitesolid (7.0 g). LC/MS System A: R_(t)=4.38 mins.

[0515] (b) 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acidamide (45)

[0516] A solution of 3-(biphenyl-4-yloxymethyl)-2-methyl-furan (44) (5g) in tetrahydrofuran (30 mL) was cooled to −78° C. with stirring andwas treated with butyllithium (2.5 M in hexanes; 9.84 mL) drop-wise over10 minutes. After stirring for 45 mins at −78° C., cooling was removedfor a period of 15 minutes then re-introduced. A stream of sulphurdioxide gas was then passed over the surface of the reaction mixtureuntil the pH of the reaction was between pH6 and pH7. Stirring wascontinued for a further 1.5 hours at −78° C. and then pentane was added(50 mL). The resulting precipitate was collected by filtration and thenre-suspended in water (75 mL). This suspension was cooled to 0° C. andtreated with sodium acetate (3.88 g) and hydroxylamine-O-sulfonic acid(2.67 g) and stirred at room temperature for 16 hours. The reactionmixture was diluted with water (300 mL) and extracted into ethyl acetate(3×250 mL). The combined organic extracts were washed successively withsaturated sodium hydrogen carbonate (300 mL) and brine (300 mL), dried,and concentrated in vacuo. This material was purified by flashchromatography, eluting with diethyl ether/petroleum ether (2:3 byvolume) to give a beige coloured solid (998 mg). A sample of thismaterial (100 mg) was further purified by HPLC to give compound 45 aswhite solid (55 mg). LC/MS System A: R_(t)=3.70 mins.

[0517] (c) 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acidbenzoylamide (46)

[0518] To a stirred solution of benzoic acid (61 mg) in a mixture oftetrahydrofuran (10 mL) and N,N-dimethylformamide (5 mL) was added4-(N,N-dimethylamino)pyridine (3.0 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (118 mg) and4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid amide (45)(206 mg). After 16 hours at room temperature the reaction mixture wasconcentrated in-vacuo, then partitioned between 0.1 M hydrochloric acid(30 mL) and ethyl acetate (3×30 mL). The combined organic extracts werewashed with brine (25 mL), dried (MgSO₄) and concentrated in vacuo. Thecrude product was purified by HPLC to give compound 46 as light beigesolid (17 mg). LC/MS System C: R_(t)=5.69 mins, m/z (ES⁻)=446 (M⁻ forC₂₅H₂₁NO₅S).

Example 14B Synthesis of4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid butyryl-amide(61)

[0519]

[0520] To a stirred solution of4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid amide (45)(50 mg, 0.146 mmoles) in dichloromethane (5.0 ml) was addedtriethylamine (261 μl, 0.189 mmoles), dimethyl-pyridin-4-yl-amine (1 mg)and butyryl chloride (19 μl, 0.184 mmoles). After stirring for 16 hoursat room temperature the reaction mixture was concentrated in-vacuo, andthe residue was purified by HPLC to give compound 61 as as an off-whitesolid (48 mg). LC/MS System C: R_(t)=3.82 mins, m/z (ES⁻)=412 ((M−H) forC₂₂H₂₃NO₅S).

[0521] By adapting the procedure of Example 14B there were preparedExamples 14C to 14E:

Example 14C 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acidphenylacetyl-amide (62)

[0522]

[0523] LC/MS System C: R_(t)=4.20 mins, m/z (ES⁻)=460 ((M−H) forC₂₆H₂₃NO₅S).

Example 14D 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid(3,5-dimethyl-isoxazole-4-carbonyl)-amide (63)

[0524]

[0525] LC/MS System C: R_(t)=3.98 mins, m/z (ES⁻)=465 ((M−H) forC₂₄H₂₂N₂O₆S).

Example 14E 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid(thiophene-2-carbonyl)-amide (64)

[0526]

[0527] LC/MS System C: R_(t)=4.06 mins, m/z (ES⁻)=452 ((M−H) forC₂₃H₁₉NO₅S₂).

Example 14F Synthesis of4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid(3-methoxy-propionyl)-amide (65)

[0528]

[0529] To a stirred solution of4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid amide (45)(50 mg, 0.146 mmoles) in N,N-dimethylformamide (4.0 ml) was addeddiisopropylethylamine (85 μl, 0.480 mmoles) then a solution of3-methoxypropionic acid (14 μl, 0.146 mmoles) in N,N-dimethylformamide(1.0 ml). O—(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (61 mg, 0.160 mmoles) in N,N-dimethylformamide (1.0ml) was added and the solution stirred at room temperature for 16 hours.The reaction mixture was concentrated in-vacuo, and the residue waspurified by HPLC to give compound 65 as as a white solid (42 mg). LC/MSSystem A: R_(t)=3.80 mins, m/z (ES⁻)=428 ((M−H) for C₂₂H₂₃NO₆S).

[0530] By adapting the procedure of Example 14F there were preparedExamples 14G to 14I:

Example 14G 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid(pyridin-3-yl-acetyl)-amide (66)

[0531]

[0532] LC/MS System D: R_(t)=5.64 mins, m/z (ES⁺)=463 ((M+H) forC₂₅H₂₂N₂O₅S).

Example 14H 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid(pyridine-4-carbonyl)-amide (67)

[0533]

[0534] LC/MS System D: R_(t)=5.85 mins, m/z (ES⁺)=449 ((M+H) forC₂₄H₂₀N₂O₅S).

Example 14I 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid(pyridine-3-carbonyl)-amide (68)

[0535]

[0536] LC/MS System D: R_(t)=5.92 mins, m/z (ES⁺)=449 ((M+H) forC₂₄H₂₀N₂O₅S).

Example 15 Synthesis of4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acidbenzoylamide (49) and 4-(4′-Methoxy-biphenyl-4-yloxymethy1)-5-methyl-furan-2-sulfonic acid(3,5-dimethyl-isoxazole-4-carbonyl)-amide (69)

[0537] (a) 3-(4′-Methoxy-biphenyl-4-yloxymethyl)-2-methyl-furan (47)

[0538] Compound 47 was prepared by adapting the procedure of Example14A(a). LC/MS System A: R_(t)=4.58 mins.

[0539] (b)4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acidamide (48)

[0540] Compound (48) was prepared from compound (47) by the procedure ofExample 14A(b). LC/MS System A: R_(t)=3.63 mins.

[0541] (c)4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acidbenzoylamide (49)

[0542] Compound (49) was prepared from compound (48) by the procedure ofExample 14B. LC/MS System C: R_(t)=5.37 mins, m/z (ES⁻)=476 (M⁻ forC₂₆H₂₃NO₆S).

[0543] (d)4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid(3,5-dimethyl-isoxazole-4-carbonyl)-amide (69)

[0544] Compound (69) was prepared from compound (48) by adapting theprocedure of example 14B. LC/MS System C: R_(t)=4.45 mins, m/z (ES⁻)=495((M−H) for C₂₅H₂₄N₂O₇S).

Example 16 Synthesis of4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylicacid (53)

[0545] (a)5-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylicacid methyl ester (51)

[0546] A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acidmethyl ester (16) (0.5 g),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.9 g) andtriphenylphosphine (2.3 g) in dry tetrahydrofuan (20 mL) under anitrogen atmosphere was cooled to 0° C. Diisopropylazodicarboxylate (1.8mL) was added drop-wise and the mixture was stirred at room temperaturefor 72 hours. After concentrating in vacuo, the residue was partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried (MgSO₄) and concentrated in vacuo. The residue wasextracted with pentane and the pentane phase was decanted andconcentrated to give compound 51 as an oil. This was used withoutfurther purification.

[0547] (b)4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylicacid methyl ester (52)

[0548] A mixture of5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylicacid methyl ester (51) (126 mg), 2M aqueous cesium carbonate (0.6 mL)and 2-iodo-5-methoxypyridine (95 mg) in 1,4-dioxan (10 mL) under anargon atmosphere was sonicated to expel traces of oxygen.[1,1′-Bis-(diphenylphoshino) ferrocene] dichloropalladium (II) (8 mg)was added and the mixture heated at 95° C. for 18 hours. After cooling,the mixture was acidified to pH6 with 1M aqueous hydrochloric acid andpartitioned between ethyl acetate and water. The organic phase was dried(MgSO₄) and evaporated to give compound 52 as an oil (70 mg), which wasused directly in the next step.

[0549] LC/MS System A: R_(t) 3.23 mins, m/z=354 ((M+H) for C₂₀H₁₉NO₅).

[0550] (c)4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylicacid (53)

[0551] Method 1

[0552] A solution of4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylicacid methyl ester (52) (118 mg, 0.33 mmoles) in dry tetrahydrofuran (10ml) was treated with potassium trimethylsilanoate (260 mg, 2.0 mmoles)and the mixture stirred under an argon atmosphere for 2 hours. Afterevaporation of the solvent the residue was purified by HPLC (gradient:18% acetonitrile/82% water containing 0.1% trifluoroacetic acid to 98%acetonitrile/2% water at a rate of 1%/min) to afford compound 53 (60 mg)as a white solid.

[0553] Method 2

[0554] A mixture of4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylicacid methyl ester (52) (70 mg) and 1M aqueous lithium hydroxide (1 mL)in tetrahydrofuran/methanol (2:1 by volume) (12 mL) was stirred at roomtemperature for 16 hours. The reaction mixture was acidified to betweenpH6 and pH7, and partitioned between ethyl acetate and water. Theorganic phase was separated, washed with brine and dried (MgSO₄). Afterremoval of the solvent, the residue was purified by HPLC. Compound 53was obtained as a solid (2.5 mg). LC/MS System A: R_(t)=2.90 mins, m/z(ES⁺)=340 ((M+H) for C₁₉H₁₇NO₅).

Example 17 Synthesis of4-[6-(4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylicacid (56)

[0555] (a) 4-(6-iodo-pyridin-3-yloxymethyl)-5-methyl-furan-2-carboxylicacid methyl ester (54)

[0556] Compound (54) was prepared from compound (16) and2-iodo-5-hydroxy-pyridine in a manner analagous to that described inExample 5(a). LC/MS System A: R_(t)=3.52 mins, m/z=374 (M+H) forC₁₃H₁₂INO₄)

[0557] (b)4-[6-(4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylicacid methyl ester (55)

[0558] Compound (55) was prepared from compound (54) by adapting theprocedure of Example 5(b). LC/MS System A: R_(t)=3.37 mins, m/z=354((M+H) for C₂₀H₁₉NO₅).

[0559] (c)4-[6-(4-Methoxy-phenyl)-pyridin-3-yloxymethyl]-5-methyl-furan-2-carboxylicacid (56)

[0560] Compound (56) was prepared from compound (55) by adapting theprocedure of Example 16(c). LC/MS System A: R_(t)=2.79 mins, m/z(ES⁺)=340 ((M+H) for C₁₉H₁₇NO₅)

Example 18 Synthesis of 3-Morpholin-4-yl-propane-1-sulphonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(59)

[0561] (a) 3-Morpholin-4-yl-propane-1-sulfonic acid amide (58)

[0562] Dichloromethane (40 ml) was saturated with ammonia gas withcooling (dry ice/acetone), and then 3-morpholin-4-yl-propane-1-sulphonylchloride (279 mg, 1.23 mmoles) was added. The mixture was stirred atroom temperature for 24 hours. The mixture was filtered, the filtrateevaporated and the residue was dried at 40° C. in vacuo to affordcompound 58 (210 mg) as a gum. LC/MS System A; R_(t)=0.28 mins, m/z(ES⁺)=209 (M+H for C₇H₁₆N₂O₃S).

[0563] (b) 3-Morpholin-4-yl-propane-1-sulphonic acid[4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(59)

[0564] Compound (59) was prepared from compounds (4) and (58) byadapting the procedure of Example 2A. LC/MS System D; R_(t)=4.97 mins,m/z (ES⁺)=529 (M+H for C₂₇H₃₂N₂O₇S).

Example 19 Synthesis ofN-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide(60)

[0565]

[0566] A stirred solution of4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18) (50 mg,0.162 mmoles), 2-methyl-benzenesulphonamide (42 mg, 0.243 mmoles) and4-(N,N-dimethylamino)-pyridine (2.5 mg) in a mixture of tetrahydrofuran(8 ml) and acetonitrile (2 ml) was treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg,0.194 mmoles). The mixture was stirred at room temperature for 16 hoursunder an argon atmosphere. The reaction mixture was concentrated invacuo and the residue was purified by HPLC to afford compound 60 (20 mg)as a white solid. LC/MS System D; R_(t)=11.09 mins, m/z (ES⁺)=462 (M+Hfor C₂₆H₂₃NO₅S).

Example 20A Synthesis of4-[2-(Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (72)

[0567] (a) tert-Butyl-[2-(2-methyl-furan-3-yl)-ethoxy]-diphenyl-silane(70)

[0568] (i) A solution of (2-methyl-furan-3-yl)-acetic acid ethyl ester(11.8 g, 70.2 mmoles) in tetrahydrofuran (50 ml) was added to a stirredsuspension of lithium aluminium hydride (2.66 g, 70.2 mmoles) under anitrogen atmosphere and with cooling to 0° C. When the addition wascomplete the mixture was stirred at room temperature for 3 hours, thenquenched by the addition of excess acetone. After acidifying with 10%aqueous hydrochloric acid the mixture was extracted three times withdiethyl ether. The combined extracts were dried and evaporated to affordcrude 2-(2-methyl-furan-3-yl)-ethanol as a yellow oil.

[0569] (ii) Compound (70) was prepared in the form of a pale yellow oilfrom crude 2-(2-methyl-furan-3-yl)-ethanol (from (i)) by adapting theprocedure of Example 1(a).

[0570] (b)4-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-furan-2-carboxylicacid (71)

[0571] Compound (71) was prepared in the form of a pale yellow oil fromcompound (70) by adapting the procedure of Example 1(b).

[0572] (c) 4-[2-(Biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylicacid (72)

[0573] Compound (72) was prepared from compound (71) in an analogousmanner to the methods described in Example 1(c). LC/MS System B:R_(t)=1.86 mins, m/z (ES⁻)=321 ((M−H) for C₂₀H₁₈O₄).

Example 20B Synthesis of4-[2-(4′-Methoxy-biphenyl-4-yloxy)-ethyl]-5-methyl-furan-2-carboxylicacid (73)

[0574]

[0575] Compound (73) was prepared from compound (71) in an analogousmanner to the methods described in Example 1(c). LC/MS System B:R_(t)=1.86 mins, m/z (ES⁻)=351 ((M−H) for C₂₁H₂₀O₅).

Example 20C Synthesis of4-[2-(Dibenzofuran-3-yloxy)-ethyl]-5-methyl-furan-2-carboxylic acid (74)

[0576]

[0577] Compound (74) was prepared from compound (71) in an analogousmanner to the methods described in Example 1(c). LC/MS System B:R_(t)=1.86 mins, m/z (ES⁻)=335 ((M−H) for C₂₀H₁₆O₅).

Example 21A Synthesis of 4-(Biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (77)

[0578] (a) 4-Hydroxymethyl-furan-2-carboxylic acid (75)

[0579] A solution of furan-3-yl-methanol (1.6 g, 16.5 mmoles) in drytetrahydrofuran (25 ml) under an argon atmosphere was cooled to −78° C.and treated dropwise with n-butyl-lithium (9.2 mL, 23 mmoles of a 2.5Msolution in hexanes). After 1 hour, sec-butyl-lithium (14.0 ml, 18.2mmoles of a 1.3M solution in hexanes) was added. After stirring for afurther 4 hours at −78° C., the mixture was quenched by the addition ofa large excess of solid carbon dioxide. The mixture was allowed to warmto room temperature and was added to a mixture of ethyl acetate and 1Maqueous hydrochloric acid (60 ml). The organic phase was separated,washed with brine, dried, and evaporated. The residue was dissolved indichloromethane and on standing a cream solid precipitated. Theprecipitate was collected and dried to afford compound 75 as cream solid(0.4 g).

[0580] (b) 4-(tert-Butyl-dimethyl-silanyloxymethyl)-furan-2-carboxylicacid (76)

[0581] A mixture of 4-hydroxymethyl-furan-2-carboxylic acid (75) (1.4 g,9.85 mmoles), tert-butyl-chloro-dimethyl-silane (3.2 g, 21 mmoles) andimidazole (2.14 g, 31.5 mmoles) in dry DMF (35 ml) was stirred at roomtemperature for 24 hours. Excess methanol (˜3 ml) was added and themixture stirred for a further 3 hours. After partitioning between ethylacetate and water, the aqueous phase was acidified to pH=1 with 2Maqueous hydrochloric acid and re-extracted with ethyl acetate. Thecombined ethyl acetate phases were washed with water, dried (MgSO₄), andthe solvent evaporated to give compound 76 as a white solid (2.4 g).

[0582] (c) 4-(Biphenyl-4-yloxyvmethyl)-furan-2-carboxylic acid (77)

[0583] Compound (77) was prepared from compound (76) in an analogousmanner to the methods described in Example 1(c). LC/MS System B;R_(t)=1.72 mins, m/z (ES⁻)=293 (M−H for C₁₈H₁₄O₄).

Example 21B Synthesis of4-(Dibenzofuran-2-yloxymethyl)-furan-2-carboxylic acid (78)

[0584]

[0585] Compound (78) was prepared from compound (76) in an analogousmanner to the methods described in Example 1(c). LC/MS System B;R_(t)=1.72 mins, m/z (ES⁻)=307 (M−H for C₁₈H₁₂O₅).

Example 21C Synthesis of4-(4′-Cyano-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (79)

[0586]

[0587] Compound (79) was prepared from compound (76) in an analogousmanner to the methods described in Example 1(c). LC/MS System B;R_(t)=1.65 mins, m/z (ES⁻)=318 (M−H for C₁₉H₁₃NO₄).

Example 21D Synthesis of4-(4′-Methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (80)

[0588]

[0589] Compound (80) was prepared from compound (76) in an analogousmanner to the methods described in Example 1(c). LC/MS System B;R_(t)=1.72 mins, m/z (ES⁻)=323 (M−H for C₁₉H₁₆O₅).

Example 21E Synthesis of4-(Dibenzofuran-3-yloxymethyl)-furan-2-carboxylic acid (81)

[0590]

[0591] Compound (81) was prepared from compound (76) in an analogousmanner to the methods described in Example 1(c). LC/MS System B;R_(t)=1.75 mins, m/z (ES⁻)=307 (M−H for C₁₈H₁₂O₅).

Example 22A Synthesis of4-(Biphenyl-4-yloxymethyl)-5-isopropyl-furan-2-carboxylic acid (85)

[0592] (a) 2-Isopropyl-furan-3-carboxylic acid ethyl ester (82)

[0593] An ice-chilled solution of sodium hydroxide (1.9 g) in water (25ml) was added, during 40 minutes, to a stirred solution of4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15ml) with ice bath cooling. When the addition was complete the mixturewas stirred rapidly for 1 hour, then the ethereal layer was separated,washed with water and dried. Evaporation of the solvent gave a yellowoil, which was purified by flash chromatography using a gradient elutionfrom neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to affordcompound 82 as an oil (2.4 g).

[0594] (b) Tri-isopropyl-(2-isopropyl-furan-3-ylmethoxy)-silane (83)

[0595] (i) A solution of 2-isopropyl-furan-3-carboxylic acid ethyl ester(82) (4.0 g, 21.95 mmoles) in tetrahydrofuran (70 ml) was treatedportionwise during 0.5 h with lithium aluminium hydride (0.7 g, 18.4mmoles) under a nitrogen atmosphere. When the addition was complete themixture was stirred at room temperature for 18 hours, then quenched bythe addition of excess acetone (1 ml) and then water (1 ml). Afterdiluting with ethyl acetate (150 ml) the grey precipitate was removed byfiltration. The filtrate was evaporated and the residue dissolved indiethyl ether and dried. Evaporation of the solvent afforded(2-isopropyl-furan-3-yl)-methanol. This material was used immediately inthe next step.

[0596] (ii) A solution of the (2-isopropyl-furan-3-yl)-methanol from (i)in dry dichloromethane (120 ml) was treated withchloro-tri-isopropyl-silane (5.2 g, 27.0 mmoles) and imidazole (3.0 g,44.0 mmoles) and the mixture was stirred overnight at room temperature.The reaction mixture was washed sequentially with 2M aqueoushydrochloric acid, water, saturated aqueous sodium bicarbonate, waterand brine. After drying, evaporation of the solvents afforded acolourless oil, which heated at 125° C. under reduced pressure (10millibars). The residue was compound 83 obtained as a pale yellow oil.

[0597] (c) 5-Isopropyl-4-triisopropylsilanyloxymethyl-furan-2-carboxylicacid (84)

[0598] Compound (84) was prepared in the form of a cream solid fromcompound (83) by adapting the procedure of Example 1(b).

[0599] (d) 4-(Biphenyl-4-yloxymethyl)-5-isopropyl-furan-2-carboxylicacid (85)

[0600] Compound (85) was prepared from compound (84) in an analogousmanner to the methods described in Example 1(c). LC/MS System B;R_(t)=1.93 mins, m/z (ES⁻)=335 (M−H for C₂₁H₂₀O₄).

Example 22B Synthesis of5-Isopropyl-4-(4′-methoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (86)

[0601]

[0602] Compound (86) was prepared from compound (84) in an analogousmanner to the methods described in Example 1(c). LC/MS System B;R_(t)=1.93 mins, m/z (ES⁻)=365 (M−H for C₂₂H₂₂O₅).

Example 22C Synthesis of4-(Dibenzofuran-3-yloxymethyl)-5-isopropyl-furan-2-carboxylic acid (87)

[0603]

[0604] Compound (87) was prepared from compound (84) in an analogousmanner to the methods described in Example 1(c). LC/MS System B;R_(t)=1.93 mins, m/z (ES⁻)=349 (M−H for C₂₁H₁₈O₅).

Example 23A Synthesis of4-(Biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylic acid(90)

[0605] (a) Tri-isopropyl-(2-trifluoromethyl-furan-3-ylmethoxy)-silane(88)

[0606] (i) A solution of 2-trifluoromethyl-furan-3-carboxylic acid ethylester (2.2 g, 10.5 mmoles) in tetrahydrofuran (150 ml) was treatedportionwise during 0.5 h with lithium aluminium hydride (0.55 g, 14.5mmoles) under a nitrogen atmosphere. When the addition was complete themixture was stirred at room temperature for 18 h, then quenched by theaddition of excess acetone (1 ml) and then water (1 ml). After dilutingwith ethyl acetate (200 ml) the grey precipitate was removed byfiltration. The filtrate was dried and evaporation of the solventafforded (2-trifluoromethyl-furan-3-yl)-methanol as a colourless oil.This material was used immediately in the next step.

[0607] (ii) A solution of the (2-trifluoromethyl-furan-3-yl)-methanolfrom (i) in dry dichloromethane (180 ml) was treated withchloro-tri-isopropyl-silane (2.6 g, 13.4 mmoles) and imidazole (1.45 g,21.3 mmoles) and the mixture was stirred overnight at room temperature.Further aliquots of chloro-tri-isopropyl-silane (0.9 g, 4.64 mmoles) andimidazole (0.5 g, 7.34 mmoles) were added and the mixture was stirredfor 3 h. The reaction mixture was diluted with water, the organic phaseseparated and washed sequentially with 0.1M aqueous hydrochloric acid,water, saturated aqueous sodium bicarbonate, water and brine. Afterdrying, evaporation of the solvents afforded a colourless oil. The oilwas distilled under reduced pressure (0.05 torr) in a Kugelruhrapparatus collecting the fraction boiling at an oven temperature of125±20° C. to afford compound 88 as a colourless oil.

[0608] (b)5-Trifluoromethyl-4-triisopropylsilanyloxymethyl-furan-2-carboxylic acid(89)

[0609] A stirred solution oftri-isopropyl-(2-trifluoromethyl-furan-3-ylmethoxy)-silane (88) (2.0 g,6.24 mmoles) in tetrahydrofuran (70 ml) under argon was cooled to −78°C. and treated with sec-butyl-lithium (2.2 ml, 2.86 mmoles of a 1.3Msolution in cyclohexane). After 1 h at −78° C., excess solid carbondioxide, which had been pre-washed with tetrahydrofuran, was added andthe mixture was allowed to warm to room temperature. The mixture wasacidified to pH=4 with dilute aqueous hydrochloric acid and extractedseveral times with ethyl acetate. The combined extracts were dried(MgSO₄) and solvent removed to afford compound (89) as an off-whitesolid (1.2 g).

[0610] (c)4-(Biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylic acid(90)

[0611] Compound (90) was prepared from compound (89) in an analogousmanner to the methods described in Example 1(c). The product waspurified by HPLC. LC/MS System B; R_(t)=1.97 mins, m/z (ES⁻)=361 (M−Hfor C₁₉H₁₃F₃O₄).

Example 23B Synthesis of4-(Biphenyl-3-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylic acid(91)

[0612]

[0613] Compound (91) was prepared from compound (89) in an analogousmanner to the methods described in Example 1(c). The product waspurified by HPLC. LC/MS System B; R_(t)=1.97 mins, m/z (ES⁻)=361 (M−Hfor C₁₉H₁₃F₃O₄).

Example 23C Synthesis of4-(Dibenzofuran-2-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylic acid(92)

[0614]

[0615] Compound (92) was prepared from compound (89) in an analogousmanner to the methods described in Example 1(c). The product waspurified by HPLC. LC/MS System B; R_(t)=1.97 mins, m/z (ES⁻)=375 (M−Hfor C₁₉H₁₁F₃O₅).

[0616] Example 23D

4-(4′-Cyano-biphenyl-4-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylicacid (93)

[0617]

[0618] Compound (93) was prepared from compound (89) in an analogousmanner to the methods described in Example 1(c). The product waspurified by HPLC. LC/MS System B; R_(t)=1.89 mins, m/z (ES⁻)=386 (M−Hfor C₂₀H₁₂F₃NO₄).

Example 23E Synthesis of 4-(4′-Methoxy-biphenyl-4-yloxymethy1)-5-trifluoromethyl-furan-2-carboxylic acid (94)

[0619]

[0620] Compound (94) was prepared from compound (89) in an analogousmanner to the methods described in Example 1(c).

[0621] The product was purified by HPLC. LC/MS System B; R_(t)=1.97mins, m/z (ES⁻)=391 (M−H for C₂₀H₁₅F₃O₅).

[0622] Example 23F

4-(Dibenzofuran-3-yloxymethyl)-5-trifluoromethyl-furan-2-carboxylic acid(95)

[0623]

[0624] Compound (95) was prepared from compound (89) in an analogousmanner to the methods described in Example 1(c). The product waspurified by HPLC. LC/MS System B; R_(t)=1.97 mins, m/z (ES⁻)=375 (M−Hfor C₁₉H₁₁F₃O₅).

Example 24A Synthesis of 4-(3′,4′-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (96)

[0625]

[0626] A stirred mixture of4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester(20) (0.025 g, 0.067 mmoles), (3,4-dimethoxyphenyl)-boronic acid (0.017g, 0.093 mmoles), N,N-dimethylformamide (3 mL), potassium acetate (0.026g) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (4 mg) was stirred at roomtemperature under an argon atmosphere for 24 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The extracts werewashed with water, dried and concentrated in vacuo. The residue wasdissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (2.5mL) and 1.0 M aqueous lithium hydroxide solution (0.5 mL), and stirredfor 16 hours. The reaction mixture was acidified to pH=6 using 1Mhydrochloric acid and extracted with ethyl acetate (3×25 mL). Theextracts were dried, concentrated in vacuo and the residue purified byHPLC (gradient: 30% acetonitrile/70% water containing 0.1%trifluoroacetic acid to 70% acetonitrile/30% water at a rate of 1%/min)to give compound 96 as a solid (15 mg). LC/MS System B; R_(t)=1.65 mins,m/z (ES⁻)=367 (M−H for C₂₁H₂₀O₆).

Example 24B Alternate synthesis of4-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-5-methyl-furan-2-carboxylicacid (28)

[0627]

[0628] Compound (28) was prepared from compound (20) and(3,4-methylenedioxyphenyl)-boronic acid by adapting the procedure ofExample 24A. LC/MS System B; R_(t)=1.76 mins, m/z (ES⁻)=351 (M−H forC₂₀H₁₆O₆).

Example 24C4-(4′-Ethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(98)

[0629]

[0630] Compound (98) was prepared from compound (20) and(4-ethoxyphenyl)-boronic acid by an adapting the procedure of Example24A. LC/MS System B; R_(t)=1.86 mins, m/z (ES⁻)=351 (M−H for C₂₁H₂₀O₅).

Example 25A Synthesis of4-(2′-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(99)

[0631]

[0632] Compound (99) was prepared from compound (20) and(2-chlorophenyl)-boronic acid by adapting the procedure of Example 5(b).LC/MS System B; R_(t)=1.86 mins, m/z (ES⁻)=341 and 343 (M−H forC₁₉H₁₅ClO₄).

Example 25B Synthesis of4-(2′,6′-Difluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (100)

[0633]

[0634] Compound (100) was prepared from compound (20) and(2,6-difluorophenyl)-boronic acid by adapting the procedure of Example5(b). LC/MS System B; R_(t)=1.83 mins, m/z (ES⁻) 343 (M−H forC₁₉H₁₄F₂O₄).

Example 25C Synthesis of5-Methyl-4-(2′-trifluoromethyl-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (102)

[0635]

[0636] Compound (102) was prepared from compound (20) and(2-trifluoromethyl-phenyl)-boronic acid by adapting the procedure ofExample 5(b). LC/MS System B; R_(t)=1.93 mins, m/z (ES⁻)=375 (M−H forC₂₀H₁₅F₃O₄).

Example 25D Alternate synthesis of4-(4′-Chloro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(27)

[0637]

[0638] Compound (77) was prepared from compound (20) and(4-chloro-phenyl)-boronic acid by adapting the procedure of Example5(b). LC/MS System B; R_(t)=1.93 mins, m/z (ES⁻)=341 and 343 (M−H forC₁₉H₁₅ClO₄).

Example 25E Synthesis of4-(3′-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(104)

[0639]

[0640] Compound (104) was prepared from compound (20) and(3-fluoro-phenyl)-boronic acid by adapting the procedure of Example5(b). LC/MS System B; R_(t)=1.83 mins, m/z (ES⁻)=325 (M−H forC₁₉H₁₅FO₄).

[0641] Example 25F

5-Methyl-4-(2′-methylsulphanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (105)

[0642]

[0643] Compound (105) was prepared from compound (20) and(2-methylsulphanyl-phenyl)-boronic acid by adapting the procedure ofExample 5(b). LC/MS System B; R_(t)=1.86 mins, m/z (ES⁻)=353 (M−H forC₂₀H₁₈O₄S).

Example 26A Synthesis of4-(3′,4′-Dimethoxy-biphenyl-3-yloxymethyl)-5-methyl-furan-2-carboxylicacid (108)

[0644] (a) 4-(3-Iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acidmethyl ester (106)

[0645] A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acidmethyl ester (16) (1.85 g, 10.9 mmoles), 3-iodophenol (3.6 g, 16.35mmoles), triphenylphosphine (4.3 g, 16.35 mmoles) in tetrahydrofuran (15mL) was cooled to 0° C. Diisopropylazodicarboxylate (3.3 g, 16.35mmoles) was added and the mixture was allowed to warm to roomtemperature, then stirred for 72 h. The tetrahydrofuran was evaporatedand the residue purified by flash chromatography using hexane/ethylacetate 7:3 v/v as eluent to give compound 106 (2.8 g). This was useddirectly in step (b).

[0646] (b) 4-(3-Iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid(107)

[0647] A mixture of 4-(3-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylicacid methyl ester (106) (2.7 g, 7.25 mmoles) and lithium hydroxide (1.5g, 36.25 mmoles) in tetrahydrofuran (25 ml) containing water (2 ml) wasstirred at room temperature for 3 h. The tetrahydrofuran was evaporated,the residue was diluted with water and the mixture acidified to pH=1with 1M aqueous hydrochloric acid. The precipitate was collected washedwith water and dried at 70° C. in vacuo to give compound 107(1.76 g) asa white solid. LC/MS System B; R_(t)=3.51 mins, m/z (ES⁻)=357 (M−H forC₁₃H₁₁IO₄).

[0648] (c)4-(3′,4′-Dimethoxy-biphenyl-3-yloxymethyl)-5-methyl-furan-2-carboxylicacid (108)

[0649] (i) 2-Chlorotrityl chloride resin (2.5 g of nominal loading 1.3mmol/g) was swelled with dichloromethane (120 mL). After draining, asolution of 4-(3-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid(107) (1.16 g, 3.24 mmoles) and diisopropylethylamine (2.25 mL, 12.96mmoles) in dichloromethane (20 mL) was added and the mixture was shakenat ambient temperature for 72 hours. The resin was drained, washedsequentially with dichloromethane/triethylamine/methanol (20:1:3 byvolume) (3×30 mL), dichloromethane (4×30 mL), N,N-dimethylformamide(4×30 mL), dichloromethane (6×30 mL), and diethyl ether (3×30 mL) andthen dried at 40° C. in vacuo.

[0650] (ii) The loaded resin (110 mg) from (i) was treated with amixture of (3,4-dimethoxyphenyl)-boronic acid (119.7 mg, 0.65 mmoles),[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1) (10.6 mg) and potassium acetate (0.064 g,0.65 mmoles) in N,N-dimethylformamide (5 mL) and the mixture wasagitated at 100° C. for 24 hours. The resin was drained, washedsequentially with tetrahydrofuran/water(1:1 v/v) (2×5 mL),tetrahydrofuran (2×5 mL), N,N-dimethylformamide (3×5 mL),dichloromethane (6×5 mL) and diethyl ether (2×5 ml), then dried at 45°C. in vacuo.

[0651] The resin was treated with dichloromethane/trifluoroacetic acid(19:1 by volume) (3 mL) for 30 mins and the solution drained from theresin. This procedure was repeated. The combined solutions wereconcentrated in vacuo and the residue purified by hplc (gradient: 30%acetonitrile/70% water containing 0.1% trifluoroacetic acid to 90%acetonitrile/10% water at a rate of 1%/min) to afford compound 108(24.9mg) as a solid. LC/MS System B; R_(t)=1.69 mins, m/z (ES⁻)=367 (M−H forC₂₁H₂₀O₆).

Example 26B Synthesis of5-Methyl-4-(3′-trifluoromethyl-biphenyl-3-yloxymethyl)-furan-2-carboxylicacid (109)

[0652]

[0653] Compound (109) was prepared from compound (107) and(3-trifluoromethyl-phenyl)-boronic acid by adapting the procedure ofExample 26A(c). LC/MS System B; R_(t)=1.97 mins, m/z (ES⁻)=375 (M−H forC₂₀H₁₅F₃O₄).

Example 27A Synthesis of4-(4′-Hydroxymethyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (110)

[0654]

[0655] (i) 2-Chlorotrityl chloride resin (3.9 g of nominal loading 1.3mmol/g) was swelled with dichloromethane (40 mL). After draining, asolution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid(26) (1.78 g, 3.3 mmoles) and diisopropylethylamine (2.3 mL) indichloromethane (30 mL) was added and the mixture was shaken at roomtemperature for 72 hours. The resin was drained, washed sequentiallywith dichloromethane/triethylamine/methanol (20:1:3 by volume) (3×30mL), dichloromethane (6×30 mL), N,N-dimethylformamide (2×25 mL),dichloromethane (6×25 mL), and diethyl ether (2×25 mL) and dried at 40°C. in vacuo.

[0656] (ii) The loaded resin (110 mg) from (i) was treated with amixture of (4-hydroxymethyl-phenyl)-boronic acid (98.3 mg, 0.65 mmoles),[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1) (10.6 mg) and cesium carbonate (0.212 g, 0.65mmoles) in N,N-dimethylformamide (5 mL) and the mixture was agitated at40° C. under a nitrogen atmosphere for 72 hours. The resin was drained,washed sequentially with tetrahydrofuran/water (1:1v/v) (2×5 mL),tetrahydrofuran (2×5 mL), N,N-dimethylformamide (3×5 mL),dichloromethane (6×5 mL) and diethyl ether (2×5 ml), then dried at 45°C. in vacuo.

[0657] The resin was treated with dichloromethane/trifluoroacetic acid(19:1 by volume) (3 mL) for 30 mins and the solution drained from theresin. This procedure was repeated. The combined solutions wereconcentrated in vacuo and the residue purified by hplc (gradient: 30%acetonitrile/70% water containing 0.1% trifluoroacetic acid to 90%acetonitrile/10% water at a rate of 1%/min) to compound 110 (18.3 mg) asa solid. LC/MS System B; R_(t)=1.48 mins, m/z (ES⁻=337 (M−H forC₂₀H₁₈O₅).

Example 27B Synthesis of5-Methyl-4-(4′-methylsulphanyl-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (111)

[0658]

[0659] The loaded resin (110 mg) (from example 27A, (i)) was treatedwith a mixture of (4-methylsulphanyl-phenyl)-boronic acid (109 mg, 0.65mmoles), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (10.6 mg) and potassium acetate(0.064 g, 0.65 mmoles) in N,N-dimethylformamide (5 mL) and the mixturewas agitated at 40° C. for 60 hours. The resin was drained, washedsequentially with tetrahydrofuran/water (1:1v/v) (2×5 mL),tetrahydrofuran (2×5 mL), N,N-dimethylformamide (3×5 mL),dichloromethane (6×5 mL) and diethyl ether (2×5 ml), then dried at 45°C. in vacuo.

[0660] The resin was treated with dichloromethane/trifluoroacetic acid(19:1 by volume) (3 mL) for 30 mins and the solution drained from theresin. This procedure was repeated. The combined solutions wereconcentrated in vacuo and the residue purified by hplc (gradient: 30%acetonitrile/70% water containing 0.1% trifluoroacetic acid to 90%acetonitrile/10% water at a rate of 1%/min) to afford compound 111(5.0mg) as a solid. LC/MS System B; R_(t)=1.90 mins, m/z (ES⁻)=353 (M−H forC₂₀H₁₈O₄S).

Example 27C Synthesis of4-(3′-Hydroxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(112)

[0661]

[0662] Compound (112) was prepared from compound (26) and(3-hydroxy-phenyl)-boronic acid by adapting the procedure of Example27A. LC/MS System B; R_(t)=1.23 mins, m/z (ES⁻)=323 (M−H for C₁₉H₁₆O₅).

Example 27D4-(4′-Dimethylamino-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (113)

[0663]

[0664] Compound (113) was prepared from compound (26) and(4-dimethylamino-phenyl)-boronic acid by adapting the procedure ofExample 27B. LC/MS System B; R_(t)=1.83 mins, m/z (ES⁻)=350 (M−H forC₂₁H₂₁NO₄).

Example 27E Synthesis of5-Methyl-4-(4′-trifluoromethoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (114)

[0665]

[0666] Compound (114) was prepared from compound (26) and(4-trifluoromethoxy-phenyl)-boronic acid by adapting the procedure ofExample 27B. LC/MS System C; R_(t)=11.01 mins, m/z (ES⁻)=391 (M−H forC₂₀H₁₅F₃O₅).

Example 27F5-Methyl-4-(2′-trifluoromethoxy-biphenyl-4-yloxymethyl)-furan-2-carboxylicacid (115)

[0667]

[0668] Compound (115) was prepared from compound (26) and(2-trifluoromethoxy-phenyl)-boronic acid by adapting the procedure ofExample 27B. LC/MS System B; R_(t)=1.97 mins, m/z (ES⁻)=391 (M−H forC₂₀H₁₅F₃O₅).

Example 27G Synthesis of4-(3′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(116)

[0669]

[0670] Compound (116) was prepared from compound (26) and(3-methoxy-phenyl)-boronic acid by adapting the procedure of Example27B. LC/MS System B; R_(t)=1.79 mins, m/z (ES⁻)=337 (M−H for C₂₀H₁₈O₅).

Example 27H Synthesis of4-(3′-Acetyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(117)

[0671]

[0672] Compound (117) was prepared from compound (26) and(3-acetyl-phenyl)-boronic acid by adapting the procedure of Example 27B.LC/MS System B; R_(t)=1.69 mins, m/z (ES⁻)=349 (M−H for C₂₁H₁₈O₅).

Example 27I Synthesis of4-(4′-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(118)

[0673]

[0674] Compound (118) was prepared from compound (26) and(4-fluoro-phenyl)-boronic acid by adapting the procedure of Example 27B.LC/MS System B; R_(t)=1.79 mins, m/z (ES⁻)=325 (M−H for C₁₉H₁₅FO₄).

Example 28 Synthesis ofN-[4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-dimethylamino-sulphonamide(122)

[0675]

[0676] N,N-Dimethylsulphamide (73 mg, 0.59 mmoles),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (31 mg,0.162 mmoles) and dimethyl-pyridin-4-yl-amine (1 mg) were added to astirred solution of4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(4)(50 mg, 0.148 mmoles) in dichloromethane (20 ml). The mixture wasstirred under an argon atmosphere for 18 hours. After evaporation of thesolvent, the residue was partitioned between dichloromethane and water.The aqueous phase was separated and extracted with dichloromethane. Thecombined extracts were washed with 1M aqueous hydrochloric acid,saturated aqueous sodium bicarbonate, brine and dried (MgSO₄).Evaporation of the solvent afforded the crude product, which waspurified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1%trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min)to afford compound 122(23.5 mg) as a white solid. LC/MS System C:R_(t)=3.67 mins, m/z (ES⁻)=443 ((M−H) for C₂₂H₂₄N₂O₆S).

Example 29 Alternative synthesis of4-(4′-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(118)

[0677] (a) 3-(4-Iodo-phenoxymethyl)-2-methyl-furan (123)

[0678] 3-(4-Iodo-phenoxymethyl)-2-methyl-furan was prepared from(2-methyl-furan-3-yl)-methanol and 4-iodo-phenol in an analogous mannerto that described in Example 14(a).

[0679] (b) 3-(4′-Fluoro-biphenyl-4-yloxymethyl)-2-methyl-furan (124)

[0680] A mixture of (4-fluoro-phenyl)-boronic acid (300 mg, 2.1 mmoles),3-(4-iodophenoxymethyl)-2-methyl-furan (123) (500 mg, 1.6 mmoles) andpotassium acetate (0.6 g) in N,N-dimethylformamide (70 mL) was degassed,treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (90mg) and the mixture was agitated at 95° C. for 12 hours under an argonatmosphere. The mixture was concentrated in vacuo, partitioned betweenwater (100 ml) and diethyl ether (200 ml). The aqueous phase wasre-extracted with diethyl ether, and the combined etheral phases weredried and evaporated. The residue was purified by flash chromatography,using diethyl ether as eluent, to afford compound 124(200 mg) as asolid. This material was used directly.

[0681] (c)4-(4′-Fluoro-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(118)

[0682] A solution of 3-(4′-fluoro-biphenyl-4-yloxymethyl)-2-methyl-furan(124) (200 mg, 0.71 mmoles) in dry tetrahydrofuran (15 ml) was cooled to−70° C. and stirred under an argon atmosphere. The mixture was treateddropwise with sec-butyl lithium (0.6 ml, of a 1.3M solution incyclohexane) and stirred for 1 hour at −70° C. The reaction was quenchedby the addition of excess solid carbon dioxide and allowed to warm toroom temperature. The mixture was diluted with water, washed withdiethyl ether and the aqueous phase acidified to pH=6 withdilute aqueoushydrochloric acid. The mixture was extracted with ethyl acetate, theextracts dried (MgSO₄), and solvent removed in vacuo to give a yellowoil. The oil was purified by hplc to afford compound 118(15 mg) as asolid. LC/MS System A; R_(t)=3.71 mins, m/z (ES⁻)=325 (M−H forC₁₉H₁₅FO₄).

Example 30 Synthesis of4-(2′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(126) andN-[4-(2′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(127)

[0683] (a)4-(2′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acidmethyl ester (125)

[0684] A degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylic acid methylester (119) (200 mg, 0.54 mmoles), 1-bromo-2-methoxy-benzene (80 μl,0.65 mmoles), 2M aqueous cesium carbonate (1.0 ml) and), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complex withdichloromethane (1:1) (44 mg) in 1,4-dioxan (30 ml), under an argonatmosphere was heated at 95° C. for 18 hours. After cooling, the mixturewas concentrated, the residue dissolved in ethyl acetate and washed withbrine and dried. After evaporation of the solvent, the residue waspurified by flash chromatography using cyclohexane/ethyl acetate 9:1 v/vas eluent to afford compound 125(40 mg) as an oil. LC/MS System A;R_(t)=4.14 mins, m/z (ES⁺)=353 weak (M+H for C₂₁H₂₀O₅).

[0685] (b)4-(2′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid(126)

[0686] A solution of4-(2′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acidmethyl ester (125) (40 mg, 0.11 mmoles) in dry tetrahydrofuran (25 ml)was treated with potassium trimethylsilanoate (73 mg, 0.56 mmoles) andthe mixture stirred under an argon atmosphere for 16 h. Afterevaporation of the solvent the residue was acidified to pH=2 with 0.1Maqueous hydrochloric acid and the mixture extracted with ethyl acetate.The dried extracts were evaporated and the residue pumped under highvacuum at 40° C. to afford compound 126(29 mg) as an off-white solid.LC/MS System D; R_(t)=8.30 mins, m/z (ES⁺)=339 (M+H for C₂₀H₁₈O₅).

[0687] (c)N-[4-(2′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide(127)

[0688] Compound (127) was prepared from compound (126) by adapting theprocedure of Example 2A. LC/MS System D; R_(t)=9.17 mins, m/z (ES⁺)=478(M+H for C₂₆H₂₃NO₆S).

Example 31 Synthesis of4-(4′-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (129),N-[4-(4′-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(130) and 3,5-Dimethyl-isoxazole-4-sulfonic acid[4-(4′-difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide (131)

[0689] (a)4-(4′-difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid methyl ester (128)

[0690] A degassed mixture of5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylicacid methyl ester (119) (200 mg, 0.54 mmoles),4-difluoromethoxy-1-iodo-benzene (175 mg, 0.65 mmoles), 2M aqueouscesium carbonate (0.81 ml) and), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20mg) in 1,4-dioxan (10 ml), under an argon atmosphere was heated at 80°C. for 20 h. Further quantities of 4-difluoromethoxy-1-iodo-benzene(87.5 mg, 0.0.27 mmoles) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (10mg) were added and heating at 80° C. was continued for 4 hours. Aftercooling, the mixture was concentrated. The residue was dissolved indichloromethane and washed with water and brine, and dried. The solventwas evaporated and the residue was purified by flash chromatographyusing petrol (40-60°)/diethyl ether 9:1v/v as eluent to afford compound128(120 mg) as a wax. LC/MS System A; R_(t)=4.14 mins.

[0691] (b)4-(4′-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (129)

[0692] Compound (129) was prepared fromcompound (128) by adapting theprocedure of Example 30(b). LC/MS System C; R_(t)=8.53 mins, m/z(ES⁻)=373 (M−H for C₂₀H₁₆F₂O₅).

[0693] (c)N-[4-(4′-Difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide(130)

[0694] Compound (130) was prepared from compound (129) by adapting theprocedure of Example 2A. LC/MS System C; R_(t)=9.50 mins, m/z (ES⁻)=512(M−H for C₂₆H₂₁F₂NO₆S).

[0695] (d) 3,5-Dimethyl-isoxazole-4-sulphonic acid[4-(4′-difluoromethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(131)

[0696] Compound (131) was prepared from compound (129) by adapting theprocedure of Example 2A. LC/MS System C; R_(t)=9.47 mins, m/z (ES⁻)=531(M−H for C₂₅H₂₂F₂N₂O₇S).

Example 32 Synthesis ofN-{4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-benzenesulfonamide(132), 3,5-Dimethyl-isoxazole-4-sulfonic acid{4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-amide(133),N-{4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide(134) andN-{4-[4-(5-Methoxy-1-oxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-benzenesulfonamide(135)

[0697] (a)N-{4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-benzenesulphonamide(132)

[0698] Compound (132) was prepared from compound (53) by adapting theprocedure of Example 2A. LC/MS System D; R_(t)=7.10 mins, m/z (ES⁺)=479(M+H for C₂₅H₂₂N₂O₆S).

[0699] (b) 3,5-Dimethyl-isoxazole-4-sulphonic acid{4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-amide(133)

[0700] Compound (133) was prepared from compound (53) by adapting theprocedure of Example 2A. LC/MS System D; R_(t)=7.83 mins, m/z (ES⁺)=498(M+H for C₂₄H₂₃N₃O₇S).

[0701] (c)N-{4-[4-(5-Methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-2-methyl-benzenesulphonamide(134)

[0702] Compound (134) was prepared from compound (53) by adapting theprocedure of Example 2A. LC/MS System D; R_(t)=8.43mins, m/z (ES⁺)=493(M+H for C₂₆H₂₄N₂O₆S).

[0703] (d)N-{4-[4-(5-Methoxy-1-oxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-benzenesulphonamide(135)

[0704] A solution ofN-{4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carbonyl}-benzenesulphonamide(132) (25 mg, 0.042 mmoles) in a mixture of methanol (0.5 ml) andchloroform (1 ml) was treated dropwise with a solution of3-chloro-benzenecarboperoxoic acid (10.6 mg of 72% wt. % peracid) inchloroform (1.5 ml). After stirring for 21 hours at room temperature, afurther quantity of 3-chloro-benzenecarboperoxoic acid (8.0 mg of 72%wt. % peracid) in chloroform (1 ml) was added and the mixture stirredfor 6 hours. Another aliquot of 3-chloro-benzenecarboperoxoic acid (8.0mg of 72% wt. % peracid) in chloroform (1 ml) was added and stirringcontinued for 21 hours. The mixture was evaporated and the residue waspurified by HPLC (gradient: 25% acetonitrile/75% water containing 0.1%trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min)to afford compound 135(6 mg) as a solid. LC/MS System A; R_(t)=3.03mins, m/z (ES⁺)=495 (M+H for C₂₅H₂₂N₂O₇S).

Example 33 Synthesis of5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carboxylic acid(137) andN-[5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carbonyl]-benzenesulfonamide(138)

[0705] (a)5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carboxylic acidmethyl ester (136)

[0706] Compound (136) was prepared from compound (119) and2-bromo-pyrimidine by adapting the procedure of Example 30(a). LC/MSSystem A; R_(t)=3.43 mins, m/z (ES⁺)=325 (M+H for C₁₈H₁₆N₂O₄).

[0707] (b)5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carboxylic acid(137)

[0708] Compound (137) was prepared from compound (136) by adapting theprocedure of Example 30(b). LC/MS System D; R_(t)=6.21 mins, m/z(ES⁺)=311(M+H for C₁₇H₁₄N₂O₄).

[0709] (c)N-[5-Methyl-4-(4-pyrimidin-2-yl-phenoxymethyl)-furan-2-carbonyl]-benzenesulphonamiide(138)

[0710] Compound (138) was prepared from compound (137) by adapting theprocedure of Example 2A. LC/MS System D; R_(t)=7.50 mins, m/z (ES⁺)=450(M+H for C₂₃H₁₉N₃O₅S).

Example 34 Synthesis of4-(2′,4′-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (140),N-[4-(2′,4′-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(141) and 3,5-Dimethyl-isoxazole-4-sulfonic acid[4-(2′,4′-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(142)

[0711] (a)4-(2′,4′-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid methyl ester (139)

[0712] Compound (139) was prepared from compound (119) and1-bromo-2,4-dimethoxy-benzene by adapting the procedure of Example31(a). LC/MS System A; R_(t)=4.09 mins.

[0713] (b)4-(2′,4′-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (140)

[0714] Compound (140) was prepared from compound (139) by adapting theprocedure of Example 31(b). LC/MS System D; R_(t)=8.20 mins, m/z(ES⁺)=369 (M+H for C₂₁H₂₀O₆).

[0715] (c)N-[4-(2′,4′-Dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide(141)

[0716] A stirred solution of4-(2′,4′-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (140) (50 mg, 0.136 mmoles), benzenesulphonamide (32 mg, 0.204mmoles) and 4-(N,N-dimethylamino)-pyridine (5 mg) in a mixture oftetrahydrofuran (8 ml) and acetonitrile (2 ml) was treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg,0.163 mmoles). The mixture was stirred at room temperature for 16 hoursunder an argon atmosphere. The reaction mixture was concentrated invacuo and the residue was purified by HPLC to afford compound 141(24 mg)as a white solid. LC/MS System C; R_(t)=8.99 mins, m/z (ES⁻)=506 (M−Hfor C₂₇H₂₅NO₇S).

[0717] (d) 3,5-Dimethyl-isoxazole-4-sulphonic acid[4-(2′,4′-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(142)

[0718] Compound (142) was prepared from compound (140) and3,5-dimethyl-isoxazole-sulphonic acid amide by adapting the procedure ofExample 34(c). LC/MS System C; R_(t)=9.13 mins, m/z (ES⁻)=525 (M−H forC₂₆H₂₆N₂O₈S).

Example 35 Synthesis of4-(4′-Methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (144),N-[4-(4′-Methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(145) and 3,5-Dimethyl-isoxazole-4-sulfonic acid[4-(4′-methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(146)

[0719] (a)4-(4′-Methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid methyl ester (143)

[0720] Compound (143) was prepared from compound (119) and1-bromo-4-methoxy-2-methyl-benzene by adapting the procedure of Example31(a). LC/MS System A; R_(t)=4.24 mins.

[0721] (b)4-(4′-Methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylicacid (144)

[0722] Compound (144) was prepared from compound (143) by adapting theprocedure of Example 31(b). LC/MS System D; R_(t)=8.48 mins, m/z(ES⁺)=353 (M+H for C₂₁H₂₀O₅).

[0723] (c)N-[4-(4′-Methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide(145)

[0724] Compound (145) was prepared from compound (143) and by adaptingthe procedure of Example 34(c). LC/MS System C; R_(t)=9.40 mins, m/z(ES⁻)=490 (M−H for C₂₇H₂₅NO₆S).

[0725] (d) 3,5-Dimethyl-isoxazole-4-sulphonic acid[4-(4′-methoxy-2′-methyl-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonyl]-amide(146)

[0726] Compound (146) was prepared from compound (143) and3,5-dimethyl-isoxazole-sulphonic acid amide by adapting the procedure ofExample 34(c). LC/MS System D; R_(t)=11.29 mins, m/z (ES⁻)=509 (M−H forC₂₆H₂₆N₂O₇S).

Example 36 Synthesis of5-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-1H-tetrazole (149)

[0727] (a) 4-Hydroxymethyl-5-methyl-furan-2-carbonitrile (147)

[0728] (i) Sec-Butyl lithium (1.3M solution in cyclohexane, 57.1 ml,74.2 mmoles) was added, dropwise during 10 min, to a stirred solution of4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan (referenceexample 2A) (20.0 g, 57.1 mmoles) under an argon atmosphere and withcooling to −78° C. After stirring for an additional 45 minutes, thecooling bath was removed for 15 minutes, and then the reaction wasre-cooled to −78° C. A solution of dimethylformamide (10 ml) intetrahydrofuran (40 ml) was added during 5 minutes, the reaction mixturestirred for 2 hours at −78° C. then allowed to warm to room temperature.The reaction was quenched by the addition of saturated aqueous ammoniumchloride (200 ml). Diethyl ether (500 ml) was added the organic phasewas separated, and the aqueous phase was extracted with diethyl ether(500 ml). The combined extracts were washed with water (500 ml) andbrine (500 ml), and dried (MgSO₄). Evaporation of the solvent afforded4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbaldehyde(20.4 g).

[0729] (ii) Hydroxylamine hydrochloride (1.11 g, 16.0 mmoles) andtriethylamine (2.22 ml) were added to a solution of4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbaldehydefrom (i)(6.3 g, 16.0 mmoles) in dichloromethane (125 ml) and the mixturewas stirred at room tempreature for 17 hours. After cooling to 0° C.,2-Chloro-1,3-dimethylimidazolium chloride (2.81 g, 16.6 mmoles) andtriethylamine (4.6 ml) were added and the yellow suspension was stirredat room temperature for 24 hours. The mixture was diluted with water andextracted with dichloromethane. The combined extracts were washed with5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate andwater, and finally dried (MgSO₄). The solvent was evaporated and theresidue was purified by flash chromatography (silica,cyclohexane/diethyl ether 99:1 v/v as eluent) to afford4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbonitrileas a viscous oil, (3.75 g).

[0730] (iii) A solution of4-(tert-butyl-diphenyl-silanyloxymethyl)-5-methyl-furan-2-carbonitrilefrom (ii) (3.75 g) in tetrahydrofuran (100 ml) was cooled to 0° C. underan argon atmosphere, and was treated with a 1M solution oftetrabutylammonium fluoride in tetrahydrofuran (22 ml). The mixture wasallowed to warm to room temperature and stirred for 16 hours. Thevolatiles were removed and the residue was partitioned between ethylacetate and water. The organic phase was separarted and the aqueousphase was extracted with more ethyl acetate. The combined ethyl acetateextracts were washed with 1M aqueous hydrochloric acid and brine, anddried. The solvent was evaporated and the crude orange oil was purifiedby flash chromatography (silica, gradient elution with 0% to 40% ethylacetate in cyclohexane) to afford compound 147 as a pale yellow oil (1.3g).

[0731] (b) 4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonitrile(148)

[0732] Diisopropylazodicarboxylate (1.84 g, 10.6 mmoles) was added to asolution of 4-hydroxymethyl-5-methyl-furan-2-carbonitrile (147) (1.32 g,9.6 mmoles), biphenyl-4-ol (1.63 g, 9.6 mmoles) and triphenylphosphine(4.3 g, 16.35 mmoles) in tetrahydrofuran (50 mL) with stirring andcooling to 0° C. under an argon atmosphere. After 5 minutes, the coolingwas removed and the mixture stirred at room temperature for 16 h. Thesolvent was evaporated and the residue partitioned between ethyl acetateand water. The ethyl acetate phase was washed with brine and dried.After the solvent was evaporated, the residue was purified by flashchromatography (silica, gradient elution with 5% to 10% ethyl acetate incyclohexane) to afford compound 148 as a white solid (2.2 g). IR(powder) CN st. 2225 cm⁻¹.

[0733] (c)5-[4-(Biphenyl-4-yloxymethyl)-5-methyl-furan-2-yl]-1H-tetrazole (149)

[0734] A mixture of4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonitrile (148) (100 mg,0.35 mmoles), sodium azide (27 mg, 0.415 mmoles) and potassium carbonate(62 mg, 0.45 mmoles) in dimethylformamide (5 ml) was heated at 90° C.for 96 hours then at 120° C. for 24 hours. The mixture was evaporatedand the residue purified by HPLC to afford compound 149 as a white solid(64 mg). LC/MS System D; R_(t)=9.53 mins, m/z (ES⁺)=333 (M+H forC₁₉H₁₆N₄O₂).

Example 37 Synthesis of4-(4′-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carboxylicacid (153),N-[4-(4′-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide(154),N-[4-(4′-Difluoromethoxy-biphenyl-4-ylsulfanylmethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(155) andN-[4-(4′-Difluoromethoxy-biphenyl-4-sulfinylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide(156)

[0735] (a) 4-(4-Bromo-phenylsulphanylmethyl)-5-methyl-furan-2-carboxylicacid methyl ester (150)

[0736] Diisopropylazodicarboxylate (1.27 g, 6.3 mmoles) was added to asolution of triphenylphosphine (1.65 g, 6.3 mmoles) in tetrahydrofuran(15 ml) with stirring and cooling in an ice/water bath. A solution of4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (536mg, 3.15 mmoles) and 4-bromo-thiophenol (584 mg, 3.09 mmoles) intetrahydrofuran (5 ml) was added and the mixture stirred for 30 minutesat 0° C. then 72 hours at room temperature. The solvent was evaporatedand the residue extracted with heptane then diethyl ether. The extractswere combined and evaporated to give a yellow oil which was purified byby flash chromatography using heptane/ethyl acetate 9:1v/v as eluent.This gave compound 150(600 mg) as a white solid. LC/MS System A;R_(t)=4.12 mins.

[0737] (b)5-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulphanylmethyl]-furan-2-carboxylicacid methyl ester (151)

[0738] [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (30 mg) and4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.34 ml of a 1M solution intetrahydrofuran) were added to a degassed solution of4-(4-bromo-phenylsulphanylmethyl)-5-methyl-furan-2-carboxylic acidmethyl ester (150) (400 mg, 1.17 mmoles) in 1,4-dioxan (120 ml). Themixture was heated at 100° C., under an argon atmosphere, for 20 hours,cooled and evaporated. The residue was partitioned between ethyl acetateand water, and the organic phase washed with brine and dried (MgSO₄).After evaporation of the solvent the residue was purified by by flashchromatography, using heptane/ethyl acetate 9:1v/v as eluent, to affordcompound 151(212 mg) as a colourless oil.

[0739] (c)4-(4′-difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-methyl-furan-2-carboxylicacid methyl ester (152)

[0740] [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (12.8 mg) was added to a degassedmixture of5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulphanylmethyl]-furan-2-carboxylicacid methyl ester (151) (200 mg, 0.516 mmoles),1-difluoromethoxy-4-iodo-benzene (153 mg, 0.568 mmoles) and 2M aqueouscesium carbonate (4.12 ml) in 1,4-dioxan (15 ml). The mixture was placedunder an argon atmosphere and was heated at 100° C. for 20 hours. Aftercooling, the mixture was concentrated and the residue was partitionedbetween ethyl acetate and water, and the mixture adjusted to pH=2 with1M aqueous hydrochloric acid. The organic phase was washed with brineand dried. After evaporation of the solvent, the residue was purified byflash chromatography, using heptane/ethyl acetate 9:1v/v as eluent, toafford compound 152(126 mg) as a white solid. LC/MS System A; R_(t)=4.17mins.

[0741] (d)4-(4′-Difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-methyl-furan-2-carboxylicacid (153)

[0742] Compound (153) was prepared from compound (152) by adapting theprocedure of Example 30(b)(127 mg) as a white solid. LC/MS System D;R_(t)=10.34 mins, m/z (ES⁻)=389 (M−H for C₂₀H₁₆F₂O₄S).

[0743] (e)N-[4-(4′-Difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide(154)

[0744] Compound (154) was prepared from compound (153) and2-methyl-benzenesulphonamide by adapting the procedure of Example 34(c).LC/MS System D; R_(t)=11.61 mins, m/z (ES⁺)=544 (M+H for C₂₇H₂₃F₂NO₅S₂).

[0745] (f)N-[4-(4′-Difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide(155)

[0746] Compound (155) was prepared from compound (153) by adapting theprocedure of Example 2A. LC/MS System D; R_(t)=11.44 mins, m/z (ES⁺)=530(M+H for C₂₆H₂₁F₂NO₅S₂).

[0747] (g)N-[4-(4′-Difluoromethoxy-biphenyl-4-ylsulphinylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide(156) andN-[4-(4′-Difluoromethoxy-biphenyl-4-sulfonylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide(156a)

[0748] A solution of 3-chloro-benzenecarboperoxoic acid (22 mg of 72% wtperacid) in chloroform (3 ml) was added to a solution ofN-[4-(4′-difluoromethoxy-biphenyl-4-ylsulphanylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide(154) (50 mg, 0.092 mmoles) in a mixture of methanol (1 ml) andchloroform (2 ml). After stirring for 2 hours, the solvent wasevaporated and the residue was purified by HPLC (gradient: 45%acetonitrile/55% water containing 0.1% trifluoroacetic acid to 98%acetonitrile/2% water at a rate of 1%/min) to afford compound 156(42 mg)as a white solid. LC/MS System D; R_(t)=9.61 mins, m/z (ES⁻)=558 (M−Hfor C₂₇H₂₃F₂NO₆S₂).

[0749] Also obtained wasN-[4-(4′-difluoromethoxy-biphenyl-4-ylsulphonylmethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide(156a) (8 mg) as a white solid. LC/MS System D; R_(t)=10.24 mins, m/z(ES⁻)=574 (M−H for C₂₇H₂₃F₂NO₇S₂).

Example 38 Synthesis of4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (160),N-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-benzenesulfonamide(161) andN-[4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulfonamide(162)

[0750] (a) 4-Formyl-5-methyl-furan-2-carboxylic acid methyl ester (157)

[0751] Acetic acid 1,1-diacetoxy-3-oxo-1^(λ5)-ioda-2-oxa-indan-1-ylester (Dess-Martin reagent) (549 mg, 1.293 mmoles) in drydichloromethane was added to a solution of4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (200mg, 1.176 mmoles) in dry dichloromethane (9 ml) with cooling to 0° C.under an argon atmosphere. After stirring for 20 minutes, the mixturewas diluted with diethyl ether (40 ml) and was poured into saturatedaqueous sodium bicarbonate (30 ml) containing sodium thiosulphatepentahydrate (4 g) and agitated vigorously for 5 minutes. The organicphase was washed with saturated aqueous sodium bicarbonate (40 ml),water (50 ml) and brine (50 ml) and dried. After removal of the solvent,the residue was purified by flash chromatography, using petrol/diethylether 4:1 v/v as eluent, to afford compound 157(140 mg) as a whitesolid.

[0752] (b) 4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acidmethyl ester (158)

[0753] A solution of biphenyl-4-ylamine (150 mg, 0.883 mmoles) and4-formyl-5-methyl-furan-2-carboxylic acid methyl ester (157) (135 mg,0.803 mmoles) in methanol (2.0 ml) was stirred over molecular sieves(type 3 Å) for 1 hour. Sodium cyanoborohydride (55 mg, 0.883 mmoles) wasadded and the mixture stirred for 18 hour at room temperature. Themixture was concentrated and partitioned between ethyl acetate (25 ml)and saturated aqueous sodium bicarbonate (30 ml). The aqueous phase wasre-extracted with ethyl acetate (2×25 ml) and the combined extracts werewashed with brine (50 ml) and dried (MgSO₄). After removal of thesolvent, the residue was purified by by flash chromatography, using agradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to affordcompound 158(75 mg).

[0754] (c) 4-Chloromethyl-5-methyl-furan-2-carboxylic acid methyl ester(159)

[0755] Triethylamine (196 μl, 1.41 mmoles), followed by4-methyl-benzenesulphonyl chloride (247 mg, 1.293 mmoles) were added toa stirred solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acidmethyl ester (16) (200 mg, 1.176 mmoles) in dry dichloromethane at 0° C.under an argon atmosphere. The reaction mixture was stirred at 0° C. for15 minutes, then allowed to warm to room temperature and was stirred fora further 4 hours. The mixture was washed with saturated aqueous sodiumbicarbonate (50 ml) and brine (50 ml), and dried (MgSO₄). After removalof the solvent, the residue was purified by flash chromatography, usingpetrol/diethyl ether 19:1 v/v as eluent, to afford compound 159(75 mg)as a white solid. LC/MS System D; R_(t)=6.34 mins, m/z (ES⁺)=189 (M+Hfor C₈H₉ClO₃).

[0756] (d) 4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acidmethyl ester (158)

[0757] Potassium iodide (32 mg) and a solution of biphenyl-4-ylamine (74mg, 0.438 mmoles) in tetrahydrofuran (1 ml) was added to a mixture of4-chloromethyl-5-methyl-furan-2-carboxylic acid methyl ester (159)(75mg, 0.398 mmoles) and potassium carbonate (83 mg) in tetrahydrofuran (1ml). The mixture was stirred at room temperature under an argonatmosphere for 16 hours, and then refluxed with the exclusion of lightfor 16 hours. After cooling, the mixture was concentrated and theresidue was purified by by flash chromatography, using a gradientelution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound158(91 mg). LC/MS System A; R_(t)=3.93 mins, m/z (ES⁺)=322(M+H forC₂₀H₁₉NO₃).

[0758] (e) 4-(Biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid(160)

[0759] A solution of4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methylester (158) (91 mg, 0.283 mmoles) in dry tetrahydrofuran (5 ml) wastreated with potassium trimethylsilanoate (182 mg, 1.42 mmoles) and themixture stirred under an argon atmosphere for 3 hours. After evaporationof the solvent, the residue was purified by HPLC (gradient: 15%acetonitrile/85% water containing 0.1% trifluoroacetic acid to 55%acetonitrile/45% water at a rate of 1%/min) to afford compound 160(35mg) as a white solid. LC/MS System D; R_(t)=7.64 mins, m/z (ES⁺)=308(M+H for C₁₉H₁₇NO₃).

[0760] (f)N-[4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-benzenesulphonamide(161)

[0761] A stirred solution of4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (160) (15mg, 0.036 mmoles), benzenesulphonamide (17 mg, 0.107 mmoles) and4-(N,N-dimethylamino)-pyridine (1 mg) in a mixture of tetrahydrofuran (3ml) and acetonitrile (0.5 ml) was treated with triethylamine (5.5 μl,0.039 mmoles) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (10.5 mg, 0.053 mmoles). The mixture was stirred at roomtemperature for 19 hours under an argon atmosphere. The reaction mixturewas concentrated in vacuo and the residue was purified by HPLC to affordcompound 161(8 mg) as a white solid. LC/MS System D; R_(t)=8.84 mins,m/z (ES⁺)=447 (M+H for C₂₅H₂₂N₂O₄S).

[0762] (g)N-[4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carbonyl]-2-methyl-benzenesulphonamide(162)

[0763] Compound (162) was prepared from compound (160) and2-methyl-benzenesulphonamide by adapting the procedure of Example 38(f).LC/MS System D; R_(t)=10.39 mins, m/z (ES⁺)=461 (M+H for C₂₆H₂₄N₂O₄S).

Example 39 Synthesis ofN-(4-{[4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carbonyl)-2-methyl-benzenesulfonamide(167)

[0764] (a) 4-[(4-Bromo-phenylamino)-methyl]-5-methyl-furan-2-carboxylicacid methyl ester (163)

[0765] A mixture of 4-chloromethyl-5-methyl-furan-2-carboxylic acidmethyl ester (159) (0.5 g, 2.65 mmoles), 4-bromoaniline (2.28 g, 13.25mmoles) and potassium carbonate (0.55 g, 3.98 mmoles) in terahydrofuran(25 ml) was stirred at gentle reflux for 72 hours. The mixture wasevaporated to give a yellow residue, which was purified by HPLC toafford compound 163 as a trifluoroacetic acid salt (840 mg). LC/MSSystem A; R_(t)=3.82 mins, m/z (ES⁺)=324/326 (M+H for C₁₄H₁₄BrNO₃).

[0766] (b)5-Methyl-4-{[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamino]-methyl-furan-2-carboxylicacid methyl ester (164)

[0767] A mixture of4-[(4-bromo-phenylamino)-methyl]-5-methyl-furan-2-carboxylic acid methylester (163) (280 mg, 0.864 mmoles), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (21mg), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (240 mg, 0.950 mmoles) andpotassium acetate (250 mg, 2.59 mmoles) in dimethyl sulphoxide (6 ml)was degassed and placed under an argon atmosphere. The mixture washeated at 80° C. for 5 hours, cooled and toluene (100 ml) was added. Themixture was washed with water (50 ml) and sodium bicarbonate was addeduntil the pH=9. The aqueous phase was discarded and the tolune layerfiltered. After evaporation of the solvent the residue was purified byflash chromatography (silica, heptane/ethyl acetate 4:1v/v as eluent) togive compound 164 as an oil, which was used directly in the next step.

[0768] (c)4-{[4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylicacid methyl ester trifluoroacetic acid salt (165)

[0769]5-Methyl-4-{[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamino]-methyl-furan-2-carboxylicacid methyl ester (164) (130 mg, 0.525 mmoles) was added to a degassedmixture of 2-bromo-5-methoxy-pyridine (99 mg, 0.350 mmoles),bis-(dibenzylidene-acetone)-palladium(0) (6 mg) and triphenyl-phosphine(11 mg) in toluene/dimethylformamide 1:1 v/v (5 ml) under an argonatmosphere. Aqueous potassium carbonate (0.23 ml of a 3M solution) wasadded and the mixture was heated at 100° C. for 16 hours. The reactionmixture was concentrated and the residue was purified by HPLC to affordcompound 165(38 mg). LC/MS System A; R_(t)=2.55 mins, m/z (ES⁺)=353 (M+Hfor C₂₀H₂₀N₂O₄).

[0770] (d)4-{[4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylicacid hydrochloride salt (166)

[0771] A solution of4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylicacid methyl ester trifluoroacetic acid salt (165) (38 mg, 0.082 mmoles)in tetrahydrofuran (4 ml) was treated with potassium trimethylsilanoate(63 mg, 0.049 mmoles) and the mixture stirred at room temperature for 16hours. The mixture was evaporated to dryness and pumped under highvacuum to remove silanol volatiles. The residue was purified by HPLC toafford a residue, which was dissolved in 1M aqueous hydrochloric acid.The solution was evaporated to give compound 166 as a solid (30 mg).LC/MS System A; R_(t)=2.22 mins, m/z (ES⁺)=339 (M+H for C₁₉H₁₈N₂O₄) andm/z (ES⁻)=337 (M−H for C₂₆H₂₅N₃O₅S).

[0772] (e)N-(4-{[4-(5-Methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carbonyl)-2-methyl-benzenesulphonamide(167)

[0773] A suspension of4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylicacid hydrochloride salt (166) (30 mg, 0.08 mmoles) in tetrahydrofuran (5ml) was treated with toluene-2-sulphonamide (41 mg, 0.24 mmoles),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg,0.176 mmoles) and 4-(N,N-dimethylamino)-pyridine (10 mg, 0.08 mmoles)and the mixture stirred at room temperature for 16 hours. Triethylamine(24.3 mg, 0.24 mmoles) was added and the mixture was stirred for afurther 18 hours. The reaction mixture was concentrated and the residuewas purified by HPLC to afford compound 167 as a yellow glass (1.1 mg)).LC/MS System A; R_(t)=2.72 mins, m/z (ES⁺)=492 (M+H for C₂₆H₂₅N₃O₅S) andm/z (ES⁻)=490 (M−H for C₂₆H₂₅N₃O₅S).

Example 40 Synthesis of4-[(4′-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carboxylicacid (171),N-{4-[(4′-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carbonyl}-benzenesulfonamide(172),N-{4-[(4′-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carbonyl}-2-methyl-benzenesulfonamide(173) and 3,5-Dimethyl-isoxazole-4-sulfonic acid{4-[(4′-difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carbonyl}-amide(174)

[0774] (a) 4-Difluoromethoxy-4-nitro-biphenyl (168)

[0775] [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (250 mg) was added to a degassedmixture of 4,4,5,5-tetramethyl-2-(4-nitro-phenyl)-[1,3,2]dioxaborolane(1.67 g, 6.70 mmoles), 1-difluoromethoxy-4-iodo-benzene (2.17 g, 8.04mmoles) and 2M aqueous cesium carbonate (10.05 ml) in 1,4-dioxan (120ml). The mixture was placed under an argon atmosphere and was heated at80° C. for 20 hours. After cooling, the mixture was concentrated and theresidue was partitioned between dichloromethane-(2×200 ml) and water(100 ml). The combined extracts were washed with brine (150 ml) anddried (MgSO₄). After evaporation of the solvent, the residue waspurified by flash chromatography, using petrol (60-80°)/diethyl ether19:1v/v as eluent, to afford compound 168(1.15 g) as a beige colouredsolid.

[0776] (b) 4′-Difluoromethoxy-biphenyl-4-ylamine (169)

[0777] A solution of 4-difluoromethoxy-4-nitro-biphenyl (168) (1.1 g,4.15 mmoles) in ethyl acetate (100 ml) was hydrogenated over 10%palladium on charcoal catalyst (250 mg) using a hydrogen filled balloon.After 20 hours, the mixture was filtered through a pad of diatomaceousearth and the pad rinsed with ethyl acetate. The combined filtrate andwashings were evaporated to afford compound 169(855 mg) as a solid.LC/MS System A; R_(t)=2.87 mins, m/z (ES⁺)=236(M+H) and 277(M+Hacetonitrile adduct) for C₁₃H₁₁F₂NO.

[0778] (c)4-(4′-Difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylicacid methyl ester (170)

[0779] Compound (170) was prepared from compounds (159) and (169) byadapting the procedure of Example 38(d). (420 mg). LC/MS System A;R_(t)=4.00 mins, m/z (ES⁺)=388(M+H) and 429(M+H acetonitrile adduct) forC₂₁H₁₉F₂NO₃.

[0780] (d)4-(4′-Difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylicacid (171)

[0781] Compound (171) was prepared from compound (170) by adapting theprocedure of Example 38(e). LC/MS System D; R_(t)=9.07 mins, m/z(ES⁺)=374 (M+H for C₂₀H₁₇F₂NO₄).

[0782] (e)N-{4-[(4′-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carbonyl}-benzenesulphonamide(172)

[0783] Compound (172) was prepared from compound (171) andbenzenesulphonamide by adapting the procedure of Example 38(f). LC/MSSystem D; R_(t)=10.38 mins, m/z (ES⁺)=513 (M+H for C₂₆H₂₂F₂N₂O₅S).

[0784] (f)N-{4-[(4′-Difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carbonyl}-2-methyl-benzenesulphonamide(173)

[0785] Compound (173) was prepared from compound (171) and2-methyl-benzenesulphonamide by adapting the procedure of Example 38(f).LC/MS System D; R_(t)=10.63 mins, m/z (ES⁺)=527 (M+H for C₂₇H₂₄F₂N₂O₅S).

[0786] (d) 3,5-Dimethyl-isoxazole-4-sulphonic acid{4-[(4′-difluoromethoxy-biphenyl-4-ylamino)-methyl]-5-methyl-furan-2-carbonyl}-amide(174)

[0787] Diisopropylethylamine (60 μl, 0.339 mmoles) and a solution of4-(4′-difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylicacid (171) (50 mg, 0.103 mmoles) in N,N-dimethylformamide (1.0 ml) wereadded to a stirred solution of 3,5-dimethyl-isoxazole-4-sulphonic acidamide (55 mg, 0.308 mmoles) in N,N-dimethylformamide (5.0 ml). Asolution of O—(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (46 mg, 0.124 mmoles) in N,N-dimethylformamide (1.0ml) was added and the mixture was stirred at room temperature for 16hours. The reaction mixture was concentrated in vacuo and the residuewas purified by HPLC to afford compound 174(2 mg) as a solid. LC/MSSystem D; R_(t)=10.35 mins, m/z (ES⁺)=532 (M+H for C₂₅H₂₃F₂N₃O₆S).

Example 41 Synthesis of4-{[(4′-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylicacid (176) andN-(4-{[(4′-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carbonyl)-2-methyl-benzenesulfonamide(177)

[0788] (a)4-{[(4′-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylicacid methyl ester (175)

[0789] Iodomethane (91 mg, 0.64 mmoles) and potassium carbonate (88 mg,0.64 mmoles) were added to a solution of4-(4′-difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylicacid methyl ester (170) (62 mg, 0.16 mmoles) in N,N-dimethylformamide(10 ml) and the mixture stirred at room temperature for 36 hours underan argon atmosphere. The mixture was then heated at 35° C. for 21 hours.The mixture was partitioned between dichloromethane and water, theorganic phase separated and dried (MgSO₄). After evaporation of thesolvent, the residue was purified by flash chromatography, usingcyclohexane/ethyl acetate 99:1v/v as eluent, to afford compound 175(41mg) as a brown oil. This was used directly in part (b).

[0790] (b)4-{[(4′-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylicacid (176)

[0791] A solution of4-{[(4′-difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylicacid methyl ester (175) (30 mg, 0.07 mmoles) in dry tetrahydrofuran (20ml) was treated with potassium trimethylsilanoate (19 mg, 0.15 mmoles)and the mixture stirred under an argon atmosphere for 30 hours.Trifluoroacetic acid was added until the pH=2. After evaporation of thesolvent, the residue was purified by HPLC to afford compound 176(4.8 mg)as a white solid. LC/MS System D; R_(t)=9.42 mins, m/z (ES⁺)=388 (M+Hfor C₂₁H₁₉F₂NO₄).

[0792] (c)N-(4-{[(4′-Difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carbonyl)-2-methyl-benzenesulfonamide(177)

[0793] A stirred solution of4-{[(4′-difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylicacid (176) (21 mg, 0.054 mmoles), 2-methyl-benzenesulphonamide (19 mg,0.108 mmoles) and 4-(N,N-dimethylamino)-pyridine (1 mg) in a mixture ofdichloromethane (8 ml) and acetonitrile (2 ml) was treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.4 mg,0.060 mmoles). The mixture was stirred at room temperature for 18 hoursunder an argon atmosphere. The reaction mixture was concentrated invacuo and the residue was purified by HPLC to afford compound 177(2.9mg) as a solid. LC/MS System D; R_(t)=11.21 mins, m/z (ES⁺)=541 (M+H forC₂₈H₂₆F₂N₂O₅S).

Example 42 Biological Results

[0794] Binding Ability to Human EP Receptors

[0795] Membranes were prepared from cells stably transfected with humanEP receptor cDNA. In brief, cells were cultured to confluency, scrapedfrom culture flasks, and centrifuged (800 g, 8 minutes, 4° C.). Cellswere twice washed in ice cold homogenisation buffer containing 10mMTris-HCl, 1 mM EDTA.2Na, 250 mM sucrose, 1 mM PMSF, 0.3 mMindomethacin, pH 7.4, homogenised and re-centrifuged as before. Thesupernatant was stored on ice and pellets re-homogenised and re-spun.Supernatants were pooled and centrifuged at 40000 g, 10 minutes, 4° C.Resultant membrane pellets were stored at −80° C. until use.

[0796] For assay, membranes expressing human EP₄, EP₃, EP₂ or EP₁receptors were incubated in Millipore (MHVBN45) plates containing assaybuffer, radiolabelled [³H]PGE₂ and 0.1 to 10 000 nM concentrations ofcompounds. Incubations were performed at suitable temperatures and forsuitable times to allow equilibrium to be reached. Non-specific bindingwas determined in the presence of 10 uM PGE₂. Bound and free radiolabelwas separated by vacuum manifold filtration using appropriate washbuffers, and bound radiolabel was determined by scintillation counting.Constituents of each of the buffers are included in table 1 below.

[0797] The affinity or pK_(i) of each compound for each receptor wascalculated from the concentration causing 50% radioligand displacement(IC₅₀) using the Cheng-Prusoff equation:${Ki} = \frac{{IC}_{50}}{1 + \left( \frac{{radioligand}\quad {concentration}}{\text{radioligand}{KD}} \right)}$

[0798] This approach follows that set out in Kenakin, T. P.,Pharmacologic analysis of drug receptor interaction. Raven Press, NewYork, 2^(nd) edition. TABLE 1 Receptor EP₁ EP₂ EP₃ EP₄ Protein/well 6.5μg 8 μg   5 μg 5 μg Final 3.6 nM 3 nM 2.5 nM 1 nM [³H-PGE₂] Buffer Assay10 mM MES pH6.0; 10 mM MES 10 mM MES pH 10 mM MES 10 mM MgCl₂; 1 mMpH6.0; 10 mM 6.0; 10 mM pH6.0; 10 mM EDTA, 3 uM MgCl₂; 1 mM MgCl2; 1 mMMgCl₂; 1 mM Indomethacin EDTA EDTA, 100 uM EDTA, 3 uM GTP-gamma-SIndomethacin Wash 10 mM MES pH6.0; 10 mM MES 10 mM MES pH 10 mM MES 10mM MgCl₂ pH6.0; 10 mM 6.0; 10 mM pH6.0; 1 mM MgCl₂ MgCl₂ EDTA

[0799] The results are presented as pK_(i) values in table 2 below.TABLE 2 Compound EP₄ EP₁ EP₂ EP₃ 4 >6.5 — <5 <5 5 >7.5 — <5.5 <5 6 >8 —<5 <5 7 >6.5 — <5 <5 8 >8 — <5 <5 9 >8 — <5 <5 10 >8 — <5.5 <5 11 >7.5 —<5 <5 12 >7 — <5 <5 13 >8 — <5 <5 19 >6.5 — <5 <5 21 >6.5 — <5 <5 22 >8— <5 <5 24 >6.5 <5 <5 <5 25 >6.5 — <5 <5 27 >6 — <5.5 <5 28 >6 — <5 <537 >6.5 — <5 <5 38 >6 — <5.5 <5 39 >7 — <5 <5 40 >7 — <5 <5 42 >7 — <5<5 43 >7 — <5 <5 46 >7 — <5 <5 49 >8 <5 <5 <5 50 >5.5 — <5.5 <5 53 >5.5— <5 <5 56 >5.5 — <4.5 <5 57 >5 — <5 <5 59 >5.5 — <5 <5 60 >8 <5 <5 <561 >6 — <5 <5 62 >7 — <5 <5 63 >6.5 — <5 <5 64 >7 — <5 <5 67 >6 — <5 <568 >6 — <5 <5 69 >7 — — — 72 >5 — <5 <5 73 >5.5 — <5 <5 74 >5.5 — <5 <577 >5.5 — <5 <5 78 >5 — <5.5 <5 79 >5.5 — <5 <5 80 >6.5 — <5 <5 81 >5.5— <5.5 <5 85 >5.5 — <5 <5 86 >6 — <5 <5 87 >5.5 — <5 <5 90 >5.5 — <5 <591 >5.5 — <5 <5 92 >5.5 — <5 <5 93 >5.5 — <5 <5 94 >6.5 — <5 <5 95 >5.5— <5.5 <5 96 >5.5 — <5 <5 98 >6.5 — <5 <5 99 >6 — <5.5 <5 100 >5.5 — <5<5 102 >5.5 — <5.5 <5 104 >6 — <5.5 <5 105 >5.5 — <5 <5 108 >5.5 — <5 <5109 >5.5 — <5 <5 110 >5.5 — <5 <5 111 >5.5 — <5 <5 112 >5.5 — <5 <5113 >5 — <5 <5 114 >5.5 — <5 <5 115 >5 — <5 <5 116 >6 — <5 <5 117 >5.5 —<5 <5 118 >6 — <5 <5 122 >7 — <5 <5 126 >5.5 — <5 <5 127 >7 — <5 <5129 >7.5 — <5 <5 130 >8 — <5.5 <5 131 >8.5 — <5.5 <5 132 >7.5 — <5 <5133 >7.5 — <5 <5 134 >7.5 — <5 <5 135 >5 — <5 <5 137 >5 — <5 <5 138 >5.5— <5 <5 140 >5.5 — <5 <5 141 >6.5 — <5 <5 142 >7 — <5 <5 144 >6 — <5 <5145 >7.5 — <5 <5 146 >7.5 — <5 <5 149 >7 — <5 <5 153 >6 — <5 <5 154 >7.5— <5.5 <6 155 >6 — <5.5 <5.5 156 >5 — <5 <5 156a >5 — <5 <5 160 >5.5 —<5 <5 161 >7.5 — <5 <5 162 >8.0 — <5 <5 167 >6.5 — <5 <5 171 >6.5 — <5<5 172 >8 — <5 <5 173 >8 — <5.5 <5 174 >8 — <5 <5 176 >6.5 — <5 <5177 >7.5 — <5 <5

1. A method of treating a condition which can be alleviated byantagonism of an EP4 receptor, which method comprises administering to apatient in need of treatment an effective amount of a compound offormula (I):

or a pharmaceutically acceptable salt thereof, wherein: R² is H or anoptionally substituted C₁₋₄ alkyl group; Y is either —(CH₂)_(n)—X—,where n is 1 or 2 and X is O, S, S(═O), S(═O)₂, or NR^(N1), where R^(N1)is selected from H or optionally substituted C₁₋₄ alkyl, or Y is—C(═O)NR^(N2)—, where R^(N2) is selected from H, and optionallysubstituted C₁₋₇ alkyl or C₅₋₂₀ aryl; R³ is an optionally substituted C₆aryl group linked to a further optionally substituted C₆ aryl group,wherein if both C₆ aryl groups are benzene rings, there may be an oxygenbridge between the two rings, bound adjacent the link on both rings; Ais a single bond or a C₁₋₃ alkylene group; and R⁵ is either: (i)carboxy; (ii) a group of formula (II):

 or (iii) a group of formula (III):

 wherein R is optionally substituted C₁₋₇ alkyl, C₅₋₂₀ aryl orNR^(N3)R^(N4), where R^(N3) and R^(N4) are independently selected fromoptionally substituted C₁₋₄ alkyl; (iv) tetrazol-5-yl.
 2. The methodaccording to claim 1, wherein R² is selected from H, methyl, CF₃ oriso-propyl.
 3. The method according to claim 2, wherein R² is methyl. 4.The method according to claim 1, wherein Y is —(CH₂)_(n)—X—.
 5. Themethod according to claim 4, wherein n is
 1. 6. The method according toclaim 5, wherein X is selected from O, S and NH.
 7. The method accordingto claim 6, wherein X is NH.
 8. The method according to claim 1, whereinY is —C(═O)NR^(N2)—.
 9. The method according to claim 8, wherein R^(N2)is selected from H, and optionally substituted C₁₋₄ alkyl.
 10. Themethod according to claim 1, wherein the C₆ aryl groups of R³ areindependently selected from those derived from benzene and heteroarylgroups, where the heteroatom or heteroatoms are nitrogen.
 11. The methodaccording to claim 10, wherein the C₆ aryl groups of R³ areindependently selected from those derived from benzene, pyridine and1,3-pyrimidine.
 12. The method according to claim 1, wherein A is asingle bond.
 13. The method according to claim 1, wherein A is a C₁₋₃alkylene group.
 14. The method according to claim 1, wherein R⁵ iseither: (i) a group of formula (II):

 or (ii) a group of formula (III):


15. The method according to claim 14, wherein R is selected from anoptionally substituted C₅₋₂₀ aryl group, and an optionally substitutedC₅₋₂₀ aryl-C₁₋₇ alkyl group.
 16. The method according to claim 1,wherein the condition alleviated by antagonism of an EP₄ receptor is aprimary headache disorder.
 17. The method according to claim 1, whereinthe condition alleviated by antagonism of an EP₄ receptor is migraines.18. A pharmaceutical composition comprising a compound of formula (I):

or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier or diluent, wherein: R² is H or anoptionally substituted C₁₋₄ alkyl group; Y is either —(CH₂)_(n)—X—,where n is 1 or 2 and X is O, S, S(═O), S(═O)₂, or NR^(N1), where R^(N1)is selected from H or optionally substituted C₁₋₄ alkyl, or Y is—C(═O)NR^(N2)—, where R^(N2) is selected from H, and optionallysubstituted C₁₋₇ alkyl or C₅₋₂₀ aryl; R³ is an optionally substituted C₆aryl group linked to a further optionally substituted C₆ aryl group,wherein if both C₆ aryl groups are benzene rings, there may be an oxygenbridge between the two rings, bound adjacent the link on both rings; Ais a single bond or a C₁₋₃ alkylene group; and R⁵ is either: (i)carboxy; (ii) a group of formula (II):

 or (iii) a group of formula (III):

 wherein R is optionally substituted C₁₋₇ alkyl, C₅₋₂₀ aryl orNR^(N3)R^(N4), where R^(N3) and R^(N4) are independently selected fromoptionally substituted C₁₋₄ alkyl; (iv) tetrazol-5-yl.
 19. A compound offormula (I):

or a salt, solvate and chemically protected form thereof, wherein: R² isH or an optionally substituted C₁₋₄ alkyl group; Y is either—(CH₂)_(n)—X—, where n is 1 or 2 and X is O, S, S(═O), S(═O)₂, orNR^(N1), where R^(N1) is selected from H or optionally substituted C₁₋₄alkyl, or Y is —C(═O)NR^(N2)—, where R^(N2) is selected from H, andoptionally substituted C₁₋₇ alkyl or C₅₋₂₀ aryl; R³ is an optionallysubstituted C₆ aryl group linked to a further optionally substituted C₆aryl group, wherein if both C₆ aryl groups are benzene rings, there maybe an oxygen bridge between the two rings, bound adjacent the link onboth rings; A is a single bond or a C₁₋₃ alkylene group; and R⁵ iseither: (i) carboxy; (ii) a group of formula (II):

 or (iii) a group of formula (III):

 wherein R is optionally substituted C₁₋₇ alkyl, C₅₋₂₀ aryl orNR^(N3)R^(N4), where R^(N3) and R^(N4) are independently selected fromoptionally substituted C₁₋₄ alkyl; (iv) tetrazol-5-yl, except that whenR² is methyl, Y is —CH₂—O— and R⁵ is carboxy or C₁₋₇ alkyl esterthereof, then R³ is not:


20. The compound according to claim 19, wherein R² is selected from H,methyl, CF₃ or iso-propyl.
 21. The compound according to claim 20,wherein R² is methyl.
 22. The compound according to claim 19, wherein Yis —(CH₂)_(n)—X—.
 23. The compound according to claim 22, wherein nis
 1. 24. The compound according to claim 23, wherein X is selected fromO, S and NH.
 25. The compound according to claim 24, wherein X is NH.26. The compound according to claim 19, wherein Y is —C(═O)NR^(N2)—. 27.The compound according to claim 26, wherein R^(N2) is selected from H,and optionally substituted C₁₋₄ alkyl.
 28. The compound according toclaim 19, wherein the C₆ aryl groups of R³ are independently selectedfrom those derived from benzene and heteroaryl groups, where theheteroatom or heteroatoms are nitrogen.
 29. The compound according toclaim 28, wherein the C₆ aryl groups of R³ are independently selectedfrom those derived from benzene, pyridine and 1,3-pyrimidine.
 30. Thecompound according to claim 19, wherein A is a single bond.
 31. Thecompound according to claim 19, wherein A is a C₁₋₃ alkylene group. 32.The compound according to claim 19, wherein R⁵ is either: (i) a group offormula (II):

 or (ii) a group of formula (III):


33. The compound according to claim 32, wherein R is selected from anoptionally substituted C₅₋₂₀ aryl group, and an optionally substitutedC₅₋₂₀ aryl-C₁₋₇ alkyl group.